Dynamic acylhydrazone metal ion complex libraries: A mixed-ligand approach to increased selectivity in extraction

Article abstract of DOI:10.1002/1521-3773(20021104)41:21<4096::AID-ANIE4096>3.0.CO;2-0

The dynamic nature of metal-ligand interactions facilitates the formation of metal ion acylhydrazone complex libraries. From these libraries, metal ion complexes with two different types of ligands (1-14; R¹≠R²) are shown to have sup

Full text of DOI:10.1002/1521-3773(20021104)41:21<4096::AID-ANIE4096>3.0.CO;2-0

COMMUNICATIONS
[6] Glycosides 11 13 were synthesized by using the method of Vill et al.; V.
Vill, T. Bocker, J. Thiem, F. Fischer, Liq. Cryst. 1989,6, 349.
[7] G. Pohlenz, M. Trimborn, H. Egge, Glycobiology 1994, 4, 625.
[8] H. Alpes, K. Allman, H. Plattner, J. Reichert, R. Riek, S. Schulz,
Biochim. Biophys. Acta 1986, 862, 294.
H3C
A
X
C
C
C
O
O
O
N
N
H
N
N
H
N
N
H
[9] This value is somewhat lower than that obtained by 1H NMR
spectroscopy in CDCl3/CD3OH (92:8). The discrepancy may be due
to a slight difference in experimental conditions; for example, different
amounts of adventitious water may have been present in the two
solvent systems.
Y
N
N
N
X
H
1
2
X = Y = H
X = CH3, Y = H
3 X = H, Y = CH3
4
5 X = H, A = CH3
6 X = CH3, A = CH3
7 X = H, A = Cl
8 X = CH3, A = Cl
Z
Dynamic Acylhydrazone Metal Ion Complex
Libraries: A Mixed Ligand Approach to
Increased Selectivity in Extraction**
CH2Q
9 X = H, Z = Cl
10 X = CH3, Z = Cl
11 X = H, Z = CH3
C
O
N
N
H
C
O
N
H
12 X = CH3, Z = CH3
13 X = H, Z = tBu
Seema Choudhary and Janet R. Morrow*
N
N
14 X = CH3, Z = tBu
15 X = H, Z = OH
16 X = CH3, Z = OH
17 X = H, Z = OCH3
18 X = CH3, Z = OCH3
19 X = H, Z = phenyl
20 X = CH3, Z = phenyl
X
N
Metal ion coordination chemistry is well suited to dynamic
X
3]
combinatorial chemistry approaches.[1 Diverse metal ion
21 X = H, Q = H
complex libraries can be created simply by mixing a labile
metal ion with different ligands.[4] If ligand exchange is rapid,
these metal ion complexes form the equilibrating components
of a dynamic library. The equilibrium between complexes may
be shifted upon addition of molecular targets. For example,
small molecule or biopolymer targets perturb the equilibrium
between metal ion complexes to increase the concentration of
22 X = CH3, Q = H
23 X = H, Q = phenyl
24 X = CH3, Q = phenyl
25 X = CH3, Q = (CH2)2CH3
Scheme 1. Acylhydrazone ligands used in this study.
Table 1. Extraction of Zn2þ or Cd2þ into chloroform by acylhydrazone
ligands.
7]
the metal ion complex that best binds the target.[5 We
Metal Ligand Extracted [%][a] Metal Ligand Extracted [%][a]
previously reported on dynamic combinatorial libraries of
metal ion Schiff-base complexes of limited diversity.[8] Our
selection protocol utilizes extraction of metal ion complex
libraries from aqueous into organic solvent. In this method,
the organic solvent is the ultimate target and complexes with
the greatest stability and solubility in organic solvent versus
aqueous solution are selected.[9] Here we present studies using
acylhydrazone ligand libraries and show that these libraries
lead to improvements in efficiency and selectivity of metal ion
extraction in comparison to single ligand systems.
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Cd2þ
Cd2þ
Cd2þ
Cd2þ
1
3
5
7
25
12
3.0
9.0
54
23
20
0
21
44
0
1.8
0
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Zn2þ
Cd2þ
Cd2þ
Cd2þ
Cd2þ
2
4
6
8
10
12
14
16
18
20
22
24
1
62
26
28
43
62
56
54
0
54
64
1.2
2.0
15
2.1
4.0
13
9
11
13
15
17
19
21
23
25
2
Acylhydrazone ligands (Scheme 1) were chosen to explore
the possibility of forming a double-orthogonal library[4] by
[10
exchange at metal ligand (M L) and C N bonds. 13] Initial
studies were carried out to establish the feasibility of using
these exchange processes. ZnII extracts into chloroform from a
buffered aqueous solution in the presence of two equivalents
of acylhydrazone ligand 1 (Table 1, Scheme 1). The predom-
inant complex that extracts into chloroform is the neutral
48
3.7
14
32
5
7
13
ꢀ
¼
6
8
14
[a] Extractions were carried out in 5.0 mm Mes buffer (10 mL), 0.100m
NaCl, and CHCl3 (1 mL) at 238C at pH 5.50 for ZnII (0.0500 mm) or
pH 6.50 for CdII (0.0500 mm) with 0.100 mm ligand.
complex [Zn(1ꢀ)2] as determined by comparison of H NMR
1
and mass spectral data to that of an authentic sample.
After two hours, the extent of extraction of ZnII from a
[*] Prof. J. R. Morrow, Dr. S. Choudhary
Department of Chemistry
water/chloroform mixture containing
0.0500 mm [Zn(1ꢀ)2] is identical within
University at Buffalo
R2
State University of New York
Amherst, NY 14260 (USA)
Fax : (þ 1)716-645-6963
H
N
experimental error to a second experi-
ment containing 0.0500 mm Zn(NO3)2
and 0.100 mm 1, confirming that our
system is at equilibrium. Addition of a
different acylhydrazone ligand (13) to
either of the solutions above followed
by stirring for 2 h increases the amount
O
N
N
N
N
Zn
H
E-mail: jmorrow@acsu.buffalo.edu
N
O
[**] This work was supported by the American Chemical Society
Petroleum Research Fund (34358-AC3) and by the Environment
and Society Institute of the University at Buffalo.
R1
[Zn(1-)2, R = C6H5 ]
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
4096
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4121-4096 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 21

COMMUNICATIONS
of extraction from 25 to 53%, consistent with ligand exchange
to form mixed acylhydrazone complexes. Analysis of these
mixtures by H NMR spectroscopy and by electrospray ion
mass spectrometry confirms the presence of mixed acylhy-
drazone complexes. In contrast, exchange and formation of
aldehydes show synergy in ZnII extraction in a few cases
including a 1.4-fold increase in extraction for 1 and 13 over
that expected (53% observed, 39% calculated) and 1 and 7
(43% observed, 31% calculated). Larger effects are observed
when the two classes of ligands are mixed. The percent
extraction is nearly doubled for a mixture of 6 and 7 (61%
observed, 34% calculated). Other combinations that show
significant synergistic effects include a 1.6-fold increase for 7
and 8 (64% observed, 47% calculated), a 1.4-fold increase for
5 and 6 (47% observed, 30% calculated), and a 1.3-fold
increase for 5 and 8 (58% observed, 44% calculated).
The largest synergistic effects are observed for ZnII with
ligands containing substituent variations in two positions (X
and A in Scheme 1). The fact that there are no CdII ligand
synergistic effects suggests that the size of the metal ion and
thus steric considerations are important. It is also noteworthy
that the substituent positions giving rise to synergistic effects
are those that are most likely to influence the conformation
and binding of the ligand through ligand steric effects. Methyl
groups attached to the imine carbon atom influence the
overall conformation of Schiff-base complexes[16] by reducing
the flexibility of the ligand. However, not just any combina-
tion is synergistic; acylhydrazones must have 2-aryl substitu-
ents for optimal results. Given that substituents at the 2-
position decrease the ability of the ligand to bind to the metal
ion, it is puzzling that these substituents increase the extent of
synergy in extraction. Further studies are underway to
determine the effect of these multiple ligand substituents on
ZnII complex structure.
An important goal in metal ion separations is to increase
the selectivity of the ligand for a metal ion. ZnII is normally
more easily extracted than CdII due to its higher Lewis acidity;
this is attested to by the negligible amount of CdII compared
to ZnII extracted at pH 5.5 . In fact, selectivity for ZnII versus
CdII would be higher if the two metal ions were extracted at
the same pH. Nonetheless, it is interesting that selectivity for
ZnII over CdII is enhanced for certain ligands and ligand
mixtures. For example, a combination of 5 and 6 gives a
selectivity of 12-fold for ZnII versus CdII. Additional favorable
combinations exhibiting higher selectivity include 6 and 7, 7
and 8, 5 and 8, and 6 and 8 as shown in Figure 1. Four of the
five involve combinations of ligands that are synergistic in the
1
¼
the C N bond is slow. Incubation of 1 with one equivalent of
o-toluic acid hydrazide at pD 5.9, 238C, for 14 h leads to the
1
formation of 5 (50%) as determined by H NMR spectro-
scopy. Incubation of 1, o-toluic acid hydrazide, and Zn(NO3)2
in a 2:2:1 ratio fails to produce free or bound acylhydrazone
(5) after several days. In addition, if 2-pyridinecarboxalde-
hyde and benzoic hydrazide are used in lieu of 1 for extraction
of ZnII, equilibrium is attained only after 80 h. All further
extractions used acylhydrazone ligands under conditions
ꢀ
¼
where M L exchange is dynamic but no C N exchange is
anticipated.
A library of 25 different acylhydrazone ligands was studied
for extraction of ZnII and CdII. These d10 ions were chosen
based on their flexible coordination geometries that can be
readily distorted by ligand substituents.[8] Such distortions in
coordination geometry affect the stability and solubility of the
complex. A variety of ligand substitutents were chosen with
the goal of varying the steric and electronic nature of the
ligand (Table 1). A few important trends are discussed here.
For both ZnII and CdII, acylhydrazones derived from the
ketone (compare 1 and 2) extract metal ions better than do
ligands derived from aldehydes, consistent with the extra
methyl group forming a more hydrophobic metal ion complex
with a higher molar volume. Ligands with benzyl substituents
(23, 24) extract little at pH 5.5, but efficiently at pH 8.5. This
suggests that an aryl group is necessary to lower the pKa of the
acylhydrazone ligand for extraction at acidic pH. Acylhydra-
zones with substituents in the 2-position of the aryl ring (5 8)
are less effective than analogous ligands substituted in the 4-
position (9 12), likely due to steric interference of the
substituent with binding. Ligands with methyl or tert-butyl
groups on the aryl or pyridine rings (3, 4, 11 14) do not
increase extraction over the unsubstituted derivatives (1, 2),
despite their higher molar volume.
Metal ion complex libraries are created by using two
different ligands. In these experiments, ligand exchange leads
to the formation of at least three different complexes in each
experiment ([M(L1)2], [M(L1)(L2)], [M(L2)2]); the most
stable and soluble combinations extract into chloroform. An
increase in metal ion extraction by two different ligands
compared to that by a single type of ligand is referred to as a
ligand synergistic effect.[14,15] Synergistic effects are detected
here as deviations from calculated values for the extent of
extraction (see Supporting Information). Positive deviations
arise from the formation of mixed acylhydrazone complexes
with improved extraction properties. Mixed ligand studies
are carried out in three groups; the first contains ligands
derived from ketones, the second contains ligands derived
from aldehydes, and the third is a mixture of the two types of
ligands.
No synergistic effects are observed for extraction of ZnII by
mixtures of two ligands derived from ketones. In addition, no
ligand synergistic effects are observed for extraction of CdII by
any ligand combination. However, ligands derived from
Figure 1. Comparison of percent extraction of ZnII versus CdII by mixtures
of acylhydrazone ligands. Extractions had 5.0 mm Mes buffer (10.00 mL),
0.100m NaCl, CHCl3 (1.00 mL) at 238C, at pH 5.50 for ZnII (0.500 mm) or
pH 6.50 for CdII (0.0500 mm) with 1.00 mm of each ligand.
Angew. Chem. Int. Ed. 2002, 41, No. 21
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4121-4097 $ 20.00+.50/0
4097

COMMUNICATIONS
extraction of ZnII but not CdII. The highest selectivity with
single ligands (Table 1) are 7.6-fold (6) and 3.1-fold (8).
Interestingly both 6 and 8 are ketone-derived ligands with 2-
aryl substituents, suggesting that this combination of sub-
stituents enhances extraction of ZnII.
These studies demonstrate that dynamic combinatorial
chemistry is a useful tool for the discovery of new metal ion
complexes. Synergistic interactions of ligands are useful for
building in selectivity for metal ions by using simple ligand
substituent effects. This method has potential for practical
applications given that the ligands are inexpensive and readily
synthesized. However, there remains much to learn about the
construction of an effective library of metal ion complexes.
Future work will focus on exploring strategic positions for
substitutents on different types of ligands and on increasing
the complexity of the library by using metal complexes that
bind three ligands.
[9] J. Rydberg, T. Sekine in Principles and Practices of Solvent Extraction
(Eds.: J. M. Rydberg, C. Musikas, G. R. Choppin), Marcel Dekker,
New York, 1992, pp. 101 156.
[10] G. R. L. Cousins, S.-A. Poulsen, J. K. M. Sanders, Chem. Commun.
1999, 1575 1576.
[11] G. R. L. Cousins, R. L. E. Furlan, Y.-F. Ng, J. E. Redman, J. K. M.
Sanders, Angew. Chem. 2001, 113, 437 442; Angew. Chem. Int. Ed.
2001, 40, 423 428.
[12] R. L. E. Furlan, G. R. L. Cousins, J. K. M. Sanders, Chem. Commun.
2000, 1761 1762.
[13] T. Bunyapaiboonsri, O. Ramstrom, S. Lohmann, J.-M. Lehn, L. Peng,
M. Goeldner, ChemBioChem 2001, 2, 438 444.
[14] M. L. Dietz, A. H. Bond, B. P. Hay, R. Chiarizia, V. J. Huber, A. W.
Herlinger, Chem. Commun. 1999, 1177 1178.
[15] Y. Sasaki, G. R. Choppin, J. Radioanal. Nucl. Chem. 1997, 222, 271
274.
[16] D. A. J. Voss, L. A. Buttrey-Thomas, T. S. Janik, M. R. Churchill, J. R.
Morrow, Inorg. Chim. Acta 2001, 317, 149 156.
Experimental Section
Extraction solutions were stirred in foil-wrapped vials with teflon-lined
crimp caps for 2 h and were analyzed for ZnII or CdII by use of dithizone
indicator.[8] Standard deviations in measurements are 10% or less.
Total Synthesis of Leucascandrolide A**
Alec Fettes and Erick M. Carreira*
Acylhydrazone ligands were prepared by heating a solution of either 2-
pyridinecarboxaldehyde (PCA) or 2-acetylpyridine in ethanol, a stoichio-
metric amount of the corresponding acylhydrazide, and a few drops of
hydrochloric acid. Concentration of the solution and cooling followed by
recrystallization from ethanol or ethanol/hexane yielded the ligand. In a
typical preparation, benzoic hydrazide (0.272 g, 2.00 mmol) was added to a
solution of PCA (0.190 mL, 2.00 mmol) in ethanol (20 mL) and a few drops
of hydrochloric acid was added. The solution was gently heated and stirred
for 0.25 h. Upon cooling, a white precipitate (1) formed, which was washed
with ethanol, recrystallized, and dried in vacuo. 1H NMR (400 MHz,
[D6]DMSO, 248C, TMS): d ¼ 12.0 (s, 1H; NH), 8.60 (d, 3J(H,H) ¼ 4 Hz,1H;
H10), 8.46 (s, 1H; H6), 7.92 (m, 4H; H7, H8, H1, H5), 7.60 (t, 3J(H,H) ¼
4.2 Hz, 1H; H9), 7.53 (t, 3J(H,H) ¼ 4.7 Hz, 2H; H2, H4), 7.40 ppm (t,
3J(H,H) ¼ 5.6 Hz, 1H; H3) (see Supporting Information for ligand-
numbering scheme); ESI-MS: m/z (%): 226(52) [PCA-BAHþHþ],
248(100) [PCA-BAHþNaþ].
Leucascandrolide A (1), a polyoxygenated marine macro-
lide of a new genus, was isolated in 1996 by Pietra and co-
Me
11
9
7
O
O
OMeO
O
O
17
1
N
H
N
O
O
MeO
Me
O
1
Me
[Zn(1ꢀ)2] was prepared by dissolving Zn(NO3)2 (0.788 g, 2.65 mmol) in hot
ethanol (100 mL), followed by the addition of PCA (5.30 mmol), and
benzoic hydrazide (0.721 g, 5.30 mol). Triethylamine (5.30 mmol) was
added and the solution was heated to boiling for 0.25 h. Upon cooling, a
bright yellow precipitate was recovered and recrystallized from ethanol.
1H NMR (400 MHz, [D1]chloroform, 258C, TMS): d ¼ 8.50 (s, 1H; H6),
8.21 (d, 3J(H,H) ¼ 7.6 Hz, 2H; H1, H5), 8.06 (d, 3J(H,H) ¼ 4.8 Hz, 1H;
H10), 7.72 (t, 3J(H,H) ¼ 7.6 Hz,1H; H8), 7.38 (m, 4H; H9, H2, H4, H7),
7.14 ppm (t, 3J(H,H) ¼ 5.2 Hz, 1H; H3); ESI MS: m/z (%): 513(100),
514(32), 515(63), 516(29), 517(44), [Zn(PCA-BAH)2þHþ].
workers from the calcareous sponge Leucascandra caveolata
along the east coasts of New Caledonia.[1] Despite subsequent
intensive efforts, later expeditions failed to provide additional
leucascandrolide A.[2] Leucascandrolide A (1) displays strong
cytotoxic activity in vitro on human KB and P388 cancer cell
lines (IC50 ¼ 50 and 250 ngmLꢀ1, respectively) as well as
powerful antifungal activity. An elegant total synthesis has
been recently reported by Leighton and co-workers,[3] and a
formal synthesis has been documented by Rychnovsky and
co-workers[4] along with synthetic studies of the core by
Crimmins et al.[5] and Kozmin[6] and a synthesis of the oxazole
side chain by Wipf et al.[7] The lack of availability of
Received: May 29, 2002 [Z19404]
[*] Prof. Dr. E. M. Carreira, A. Fettes
Laboratorium f¸r Organische Chemie
ETH Hˆnggerberg, HCI H-335
8093 Z¸rich (Switzerland)
[1] J.-M. Lehn, Chem. Eur. J. 1999, 5, 2455 2463.
[2] P. A. Brady, J. K. M. Sanders, J. Chem. Soc. Perkin Trans. 1 1997, 3237
3253.
[3] O. Storm, J. L¸ning, Chem. Eur. J. 2002, 8, 793 798.
[4] V. Goral, M. I. Nelen, A. V. Eliseev, J.-M. Lehn, Proc. Natl. Acad. Sci.
USA 2001, 98, 1347 1352.
Fax : (þ 41)1-632-1328
E-mail: carreira@org.chem.ethz.ch
[**] We thank the ETH, SNF, Aventis, Eli Lilly, Merck, and Hoffmann-
LaRoche for their generous support of our research program. We are
grateful to Prof. Armido Studer (Marburg) for kindly supplying the
silylated cyclohexadiene he has developed for tin-free radical
reactions.
[5] I. Huc, M. J. Krische, D. P. Funeriu, J.-M. Lehn, Eur. J. Inorg. Chem.
1999, 1415 1420.
[6] B. Klekota, M. H. Hammond, B. L. Miller, Tetrahedron Lett. 1997, 38,
8639 8642.
[7] C. M. Karan, B. L. Miller, J. Am. Chem. Soc. 2001, 123, 7455 7456.
[8] D. M. Epstein, S. Choudhary, M. R. Churchill, K. Keil, A. V. Eliseev,
J. R. Morrow, Inorg. Chem. 2001, 40, 1591 1596.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
4098
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4121-4098 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 21