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Complexes from Polyazacyclophanes Fluorescence Indicators and Metal CationsЧAn Example of Allosterism through Ring Contraction.

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[ I ] L) Seyferth. B.W. H~iines.T. G. Rucker. M. Couie. R S. Dickson. Or,qniioi i t c r a / / i < ~ s1983. 2. 472. S. Akabori, T. Kumagai. T. Shiraahige. S. Sato. K .
Kaaaroe. C' 7;iiiiura. M . Sato. ;/lid. 1987. 6 . 526: M. I. Bruce. P. A.
Humphi-cq. 0.biii Shaukataly. M. R . Snow, E. R. T. Tiekink. W. R. Cullen.
i / ~ i d .1990. '1. 2910: W. R. Cullen. S.1. Rettig. T:C. Zheng, i / d . 1992.1/. 277:
M. Snto. K . Sutuki. S. Akaori, C%On.Le/t. 1987. 2239. M. Sato. M. Sekino.
S. Akaboi-i. .I O r ~ u n o r n i Chmr.
~~.
1988. 344. C31; M . Sato. M . Sekino, i h i d .
1993. 444. 185: C' E. L. Headford. R. Mason. P. R. Ranatunge-Bandarage.
B. H. Robin\vn. J. Siinpson. J. C ' / t w i . S i c . Clicni. Coiitiiiiin. 1990, 601 : H.
W.idepohl. W. Gilm. H. Pritzkok, A. Wolf, ihid 1993. 1459. H. Wadepohl. W.
Galni. H . Prit/kow. A Wolf, A i i : ~ ~ i i( ~' / i c i i t . 1992. 104. 1050; A i i p i i . C/icnt.hi/.
&/. h t g / 1992. .i/.
1058.
[?I S. 'Rinah.i. T. Ymhida. T. Adachi. T. Yoshida. K. Onitsuka. K Sonogashira,
C / i ~ ~ i ILi r. , i / .
1994.
877.
[3] 1.D:iv.oodi. C . Eaborn. A. Pidcock. J Or'qunonwr. C/iwi. 1979. 170, 95.
[4] 1. \b: Gilje. H. u' Roesky. Cliciii. Rcr 1994. 94. X95.
[j]G W. Bushnell. K . R. Dixon, R. G. Hunter, J. J. McFarland, CUII..I Chwi.
1972. 50. 3693. K. E. Fakley. A. Pidcock. J C'hein. Soc. Dalroti Puns.1977.
1444: S Wiinmer. P Castan. F. L. Wiminer. N . P. Johnson. ihid. 1989. 403.
[h] G . Liipe~.J R u i ~ :G
. Garcia. J. M. Marti. G. Sinchez. J. Garcia. ./. OrgrtnomPr.
( ' / i w r . 1991. 412. 135, V. V. Grusliin. H. Alper. Or~uiiornerollic~
1993. 12. 1890.
[7] U . Kolle. J. Kmwkowcki, N. Klaff. L. Wesemann, U. Englert. G . E. J. Herbcrlch. ,411,qcit C'/WJI. 1991. 103. 732. Angcw. Chein. /{I/. Ed. O i g l . 1991. 30.
640:'ll-Y Dong. H:M. Lin. M.-Y. Huang. T.-Y. Lee. L.-H.Tseng. S.-M. Peng.
G H . Lee. .I O i ~ g u i i m i i ~ Cr .h c d i i i . 1991. 414. 227.
11 dd:i I'or 2c: 0.X0 xO.60 x0.10 inm, monoclinic. space group P2,ju.
. 3 6 l l ) . h=17.64(2). <.=38.313(X)A. / j = 9 7 . 0 4 ( 3 ) . Y=12311(16)A3,
= 51.06cm-'. u - 2 0 scan, 6 0 < 2 8
= 1.608 g c m '. p(Mokz)
< 50 1 All iioii-hydrogcii atoms M-ere refined anisorropically by full inatrix
leasi \qu;ires i-clinement against I F / ' . R = 0.040 and RII.= 0.045 for 8717
retlections with I > 6.Ori(/) out of 17916 unique reflections (reflection:
pnraiiieter ratio = 6.96). empirical absorption correction using DIFABS [ I l l .
(;OF = 3 07. re\idu;il electron density = - 0.89 to I . 0 4 e k 3 . For 7: 0 . 7 0 ~
0.30 x 0.10 iiini. inonoclinic. space group P2,;i,, (I = 10.22(2). h = 24.907(7).
A./l = 96.00(7) . I,'= 5614(11) A 3 . Z = 4 . / ~ < =~1, 711
~ ~ gem-'.
[, = --.175(9)
73
/r{Mok,) = 54.73 cni- I . iu-20 scan. 6.0 < 26 < 45.1 . All non-hydrogen
iitoiiis uzrc rclined anisotropically by full matrix least squares refinement
:igaiiist 1 k.1 I , R = 0.038 and R M = 0.041 for 4449 reflections with I > 9.00(1)
out (if 7564 iinique retlections (reflection:parameter ratio = 7.10). empirical
a h ~ o r p t ~ oc~irrection
n
using DIFABS 1121. GOF = 3.17. Further details o f t h e
cr>\t:iI ~ t r u c t u r emay be obtained from the Director ofthe Cambridge Crystal1ogr:iphi~('entrr. 1 2 Union Road. GB-Cambridge CBZ 1EZ ( U K ) , on quoting
the Itill Iouriiiil citation.
191 (;. Lhpe/. J. R U M , C;. Garcia, C. Vicente. J. M. Marti, .I.
A. Hermoso. A. Vegas.
M. ~l.lartiiie~-Ripoll.
J Choii. So<,.nulroit T,.oii.v. 1992. 53.
[lo] G. W. Bu\hnell. Cm. ./. Ciriwi. 1978. 56. 1773.
[I I ] R. E. Holland\. .A. G. Osborne. R. H. Whiteley. C . J. Cardin. J. C/iem. Soc.
Du/i(iii / ; u i i \ . 1985. 1527.
[12] N Wilhcr. D S t u x t . Acici Cri.,$tu//rixi..S~YY.A 1983, 39. 15X.
Complexes from Polyazacyclophanes,
Fluorescence Indicators, and Metal CationsAn Example of Allosterism through Ring
Contraction**
Ralf Baldes and H a n s - J o r g Schneider'"
Synthetic host --guest systems can be relatively easily designed
to have ;I receptor containing several conformationally strongly
coupled binding sites that may also bind organic substrates."'
We report here on ternary complexes in which the cavity for a
lipophilic guest molecule is fitted spacially by contraction of the
hollow space. which is initiated by the binding of metal cations.
[*I
Prof. Dr. ll.-.l Schneider. DiplLChem. R. Baldes
Fnchriclitiiiig Orpnische Cheiiiie der Universitat des Saarlandes
D-66114 Saarhrucken (German))
Telefax: lnt. code (681J4105
+
[**I
Molecular mechanics simulations (force-field CHARMm l3I)
of polyazacyclophanes 1 and 2 (Scheme 1 ) -obtained by published
indicate an almost spherical shape with a
Supranioleculnr Chemistry. Port 51. This work wac supported by the Deutsche
Forscliuiig\geiiieinscha~~
and the Fonds der Chemischen Industrie. We would
likc to th.iiik tlic rcfcrees for their valuable suggestions regarding references.
Par1 511- tl.-J. Schiicider. M Wang, .I Orx. C/toii. 1994. 59. 7473
1
L
3 8
36
HN
NH
3
4
Scheme I . Structures of the host ligdnds L and guest rnoleculcs G (fluorescence
indicators) and their equilibrium constants (in units of 1 0 - 3 ~' . water. 25 C ) for
the ternary complex L . G - Z n z t .
wide cavity in the absence of complexing metal cations (Fig. la).
When metal ions, for example zinc ions, are bound to the
ethylene diamine moieties, the cavities become smaller and more
strongly anisotropic (Fig. 1b), thus allowing an optimal enclosure
of guest molecules of the naphthalene type (Scheme 2, Fig. Ic).
The potential energy necessary for the formation of the smaller
cavity is provided by the high stability constant^'^] of metal
complexes of the corresponding polyamine ligands. Unfortunately, the complexes of the new derivatives of I and 2 with
biphenyl instead of benzene moieties (3 and 4, Scheme 1) are too
insoluble in water. and we can only discuss here the allosteric
properties of the well-known'*] polyazacyclophanes 1 and 2.
Because of the low solubility of these systems, the complexation
reactions could not be monitered by NMR spectroscopy. However, using fluorescence spectroscopy and suitable indicators"]
(ANS (8-anilinonaphthalene-1 -sulfonic acid), TNS (h-p-toluidino)-2-naphthalenesulfonic acid), DNSA (5-dimethylaminonaphthalene-2-sulfonic acid). Scheme I ) , the expected cooperative effects could be quantified. At the same time this presented
new possibilities for the detection of. for example. zinc ions in
aqueous solution.
The addition of a solution of 1 ( 5 x l K 3 ~at, pH 7.0 present
as 1 x 4 H + ) with ZnCl, ( 5 x
M) to a solution o f the fluorescent dye DNSA ( 1 OWs M) in water at pH 7.0 led to a considerable
increase in the fluorescence emission F ; from the saturation
curve (Fig. 2) a constant KT = 1.1 x 1 0 ' ~ with
~ ' a scattering of
about 8 YOcould be calculated for the formation of the ternary
complex L . G . M ( I . D N S A . Z n 2 + ) from a nonlinear fitting
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L&
OO
1
3
2
c (Zn")
4
MI
5
+
Fig. 2. Complex titration of DNSA ( I V ' M ) with a 1 : I mixture of 1 and ZnCI,
(both 5 x ~ O - ' M : water, 25 C. pH 7.0); fluorescence intensity in relative units,
experimental values (corrected. see text) and nonlinear fitting for a 1:l complex
(continuous line).
Fig. 1. Force-field-optimized
(CHARMm [3]) structure of
a) host 1 without a metal ion.
b) I with a zinc ion. c) the
complex of 1 ANS . Zn2+
a s space-filling model-the
enclosed naphthalene ring is
visible in the cavity.
on the basis of a 1 :1 model. When only 1 was added, the increase
of F was, at most, 4 % compared to the effect obtained
from the formation of the ternary complex; nevertheless, this
was taken into account in the calculation on the basis of linear
calibration curves (Y > 0.99), along with the slight decrease in
the concentration of DNSA during the titration. Control experiments showed that both Z n 2 + and 1 alone have a negligible
effect on the F values of DNSA, which implies that the complex-
.
ation of DNSA in the absence of the metal ion acting as an
allosteric effector is immeasurably small. On the basis of the
increase in F from 1 and DNSA alone, which hardly exceeds the
statistical error, the maximum value of the formation constant
of the binary complex in the absence of metal ions can be estimated to be below KH= 5 - 1 0 ~ - ' . Thus, the value of the relative constant of the ternary complex of at least K,,, = KT/
KH= lo2 demonstrates a greater level of cooperation than in
many other synthetic systems.['l A distinctly smaller value is
usually found for allosteric proteins.[61
All the host molecules L investigated have binding sites for
two metal ions M. Indeed, a UV/vis titration with CuSO, indicates a composition M,L, in particular for the more strongly
binding tricyclic 2 (Fig. 3). However, not only the complex titration discussed above, but also a separate experiment (Fig. 4)
indicated that a ternary complex with one metal ion is the dominant species. The simultaneous binding of an organic substrate
in the ternary complex leading to a deformation of the second
metal binding site is in agreement with molecular mechanics
simulations, which indicate the instability of the corresponding
X-
Scheme 2. Principle of the formation of ternary complexes through contraction of
the metal-free macrocycle L after addition of metal cations M.
322
VCH Veriugsgeset'lschufi mhH, D-694S1 Weinheim. 1995
Fig. 3. Dependence of the UV/vis-extinction on the molar ratio X of Cu2+ to
ligdnd; this shows a 2: 1 (M,L) stoichiometry for the complexes of Cu2' with 1 and
2; extinction at 620nm (for 1. E = 91.9 Lmo1-Icm-I) or at 860nm (for 2,
8 = 154 mol-'cm- ').
0570-0X33/95/C~303-0322
S 10.00f .25/0
Angea. Chem. Int. Ed. Engl. 1995, 34, No. 3
COMMUNICATIONS
200 I
0
o
o
0
0
o
0
0
3
loo!
:
A possible application of the ternary complexes lies in the
exploitation of the high sensitivity of fluoresence spectroscopic
methods for the determination of the concentration of metal
ions. Figure 5 shows that the concentration of Zn" in the region of
to 1 0 - 4 ~is directly proportional to the fluorescence intensity.
Designed conformational coupling in synthetic complexes between heterotopic binding sites should allow the development of
allosteric systems with potential technical and biological/medicinal applications. These systems can have considerably greater
cooperativity than that possible in biopolymers.
Reccived. July 23. 1994
Revised version: October 25. 1994 (27165 1Ej
German version: Anyew C'h(wi. 1995. 107, 3x0
c
-
50
I
Keywords: allosterism . azacyclophanes fluorescent sensors
host-guest chemistry
I-
0
1
2
c (Zn")
3
5
4
MI
----f
Fig. 4. Dcpendenceot'the tluorescenceintensity ofamixtureofDNSA(5 x 10.'~)
and I ( S x 1 0 - ' ~ )on the ZnCI, concentration; shows the l : l : l ( L ' M ' G ) stoichiometry of the ternary complexes (for further information see the legend of
Fig. I ) .
L . G 2 M (1 DNSA . 2 Z n 2 + )complex. In this respect, the system described above is positively cooperative with regard to the
ternary complex, but it is negatively cooperative with regard to
a theoretical quaternary complex L ' G ' M , (1 ' D N S A - 2 Z n 2 + ) .
The anionic substituents of the indicators ANS and TNS
should lead to a further increase in the level of cooperation.
Whilst the ternary complex with the electoneutral DNSA can
only benefit from solvophobic and/or van der Waab binding
forces in the allosteric closure of the lipophilic pocket, ionized
substrates such as ANS and T N S can call on additional electrostatic energy in the sense of a cocomplexation. Indeed, the corresponding constants, which, as for DNSA, were obtained from
the saturation curves after correction by linear calibration
curves, show a four- to sixfold increase in the formation constants of the ternary complexes (Scheme 1); the cooperativities
with ANS and TNS increase to at least K,,, = lo3. (Problems of
solubility limited the measurement to the determination of the
constants for 3 and 4 shown in Scheme 1.)
"'
[l] Previous work on allosteric host-guest complexes with organic substrates: a ) F.
Diederich. M. R. Heester. M . A. Uyeki, Angrw. Chrm. 1988. 100. 1775: Angcw.
Chem. Inr. Ed. E q f . 1988,27. 1705; b) H.-J. Schneider. D. Ruf. ;hid. 1990, 102.
1192 and 1990, 29. 1159; c) P. Scrimin, P. Tecilla. U. Tonellato. N . Vignaga, J.
Chrm. Sot.Chmm. Commun. 1991,449; d ) R. B. Sijbcsma. R. J. M. Nolte. J. Am.
Chrm. Soc. 1991.113.6695:e) M. T. Reetz, C. M. Niemeyer. K. Harms. Angew.
Chrm. 1991. 103. 1515; Angew. Chrm. Inr. Ed. Engf. 1991, 30, 1472; f) H.-J.
Schneider. F. Werner, J. Chem. Soc. Chrm. Commun. 1992. 490; g) M. Inouye.
T. Konishi, K. Isagawa, J. An,. Chon. Sot.1993, /IS,8091: h) H.-J. Schneider,
D. Giittes. U . Schneider, ibid. 1988, 110. 6449; i) J.-L. Pierre. G. Gagnaire. P.
Chautemps. Etrahcdron Lerr. 1992, 33, 217; G. Gagnaiie, G. Gellon. L L .
Pierre, {bid. 1988. 29, 933: j ) P. Marsau, H. Andrianatoandro, T. Willms, J.-P.
Desvergne, H. Bouas-Laurent, H. HopC R Utermohlen, C h m . BPY.1993. 126,
1441. k ) H. Bauer. J. Briaire. H. A. Staab. Tetruhedron Lrrr. 1985, 26. 6175; H.
Bauer. V. Matz. M. Lang, C. Krieger, H. A. Staab, Chon. Bcr. 1994. /27, 1993,
and references therein.
[2] D. Chen, A. E. Martell, Z,truh<,drun 1991, 47. 6895, and references therein.
[3] A. T. Briinger. M. Karplus, Acc. Chem. Rrs. 1991, 24, 54.
[4] P. Paoletti. Pure Appf. Chem. 1984, 56. 492, and references therein.
[5] Application of fluorescent dyes for the investigation of cyclophane inclusion
compounds: K. Odashima. K. Koga in ('vchphuncs. Yo/. 2 (Eds.: P. N. Kuhn,
S. M. Rosenfeld). Academic Press, New York, 1983, pp. 629-677: I. Tabushi.
K. Yamamura. Top. Curr. Chem. 1983. 113. 145: Y. Murakami. {hid. 1983, 115,
107. and references therein.
[6] In proteins a cooperativity of K,,, > 10 is regarded as strong: G. H. Crerlinski.
Eiophvs. Chm7. 1989, 34, 169. and references therein.
Preparation and Detection of Enantiomerically
Enriched and Configurationally Stable
a-Thioalkyllithium Compounds
t
Bernd Kaiser and Dieter Hoppe*
Dedicated to Projissor Wolfgang Liittke
on the occasion ofhis 75th birthduy
Chiral r-alkylthioalkyllithium compounds are, in contrast to
their a-alkoxy analogues, configurationally instable even at
- 80 'C.['] The causes and mechanisms of the configurational
conversions have been thoroughly investigated.l'l For example,
using racemic 1 -arylthioalkyllithium compounds, Hoffmann et
al.[lflshowed that sterically demanding aryl groups on the sulfur
atom raise the barrier to configurational inversion and that the
i
' 5O I
[*I
Fig. 5. Dependence of the fluorescence intensity of a mixture of ZnCI,, DNSA
(5 x l o - % ) and 1 (5 x W 3 M ) on the ZnC1, concentration (maximum 2 x 1 0 - 4 ~ )
(for further information see the legend of Fig. 2).
Angriv. Chcm. Inr. Ed. Engl. 1995. 34, Nu. 3
0 VCH
[**I
Prof. Dr. D. Hoppe, B. Kaiser
Organisch-Chemisches Institut der UniversitHt
Correnstrasse 40. D-48149 Miinster (Germany)
Telefax: Int. code + (251)83-9772
This work was supported by the Fonds der Chemischen Industrie and the
Deutsche Forschungsgemeinschaft.
VerlagsgeseIIschuf/ mhH, 0-69451 W<,inhrim,1995
U57U-O833/Y5/U3U3-~J323
$ /U.UO+ 2 ' 0
323
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example, contractile, fluorescence, metali, polyazacyclophanes, cationsчan, ring, complexes, indicators, allosteric
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