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Double Lewis Acid Activation in Phosphate Diester Cleavage.

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E-xperinient a/ Procedure
Ozone adsorbed on silica gel at - 78 C was passed very slowly between - 5 0
- 60 'C through a solution of Br2 in CFCI, with a stream of argon. until the
brown color of the bromine in solution had almost disappeared. The lemon-ycllow solid was freed from solvent and ozone under vacuum and dissolved in ii
little CH,CI, at - 78 C. The undissolved colorless bromine oxide was removed
by low-temperature centrifugation When the orange solution wiis cooled to
- 90 C. Br,O, crystallized in needles of the same color. R a m a n spectrum
(solid. krypton ion laser. 647.0 nm). i. = 156. 167 m. sh. 325 OJ BrOZ)s. 387 w.
449 v(Br0Br) s. 588 v(Br0Br) s. X49 v(Br0,) s. 890 v,,.(BrOL)M cm '. Crystal
structure analysis: o =1186.6(2), h =762.9(1). = 869.3(2) pm. /j =106.4(1) .
T = -145 C. P2,'c. Z = 8, / i = 20Xcm-'. 3029 measured reflections in the
range 11 = 2 -35 . + / I , + k , + I, 2800 unique reflections. R,,, = 0.020. 2302 reflections with 12 3a(/). R = 0.046. R, = 0.039. Further details of the crystal
structure investization may be obtained from the Fachinformationstentrum
Karlsruhe. Gesellschaft fur wissenschaftlich-technischeInformation mbH. D(FRG), on quoting the depositor! number
76344 Eg_pen~tein-Leopoldshafen
CSD-57429. thc names of the authors. and thc journal citation.
Fig. 1. The structure of' Br-0-BrO,
I . (ORTEP plot. thermal ellipsoids at
50% probability level). Distances [pm] and angles 1 I: Brl-011 184.9(5). Brl0 1 2 161.1(5), Brl-013 162.0(5), Br2-011 184.9(5). Br3-021 186.0(5). Br3-022
161.0(4). Br3-023 160.5(4). Br4-021 184.1(4). 81-2...Br4 299.5(1): 011-Brl0 1 2 103.0(?). 0 1 I-Brl-013 103.2(2), 012-BrI-013 106.4(3), Brl-011-Br2
I1 1.2(2l.Oll-Br3-022 103.5(2). 021-Br3-023 102 X(2). 022-Br3-023 108.8(2).
Br3-021-BI-41 I l l ( ? ) . 0 1 1 - B r Z - ' . B r 4 175.9(2). 021-Br4...BrZ 86.4(2).
few covalent bromates like O,BrONO, , [ I h 1 O,BrOCIO, ," 'I
and C,F,BrO,~lS1are known. Crystal structure analyses of
these compounds have not yet been reported.
The new bromine oxide 1 has bond lengths and bond
angles in accord with the formula Br-0-BrO,. that is, 1 has
Br" in a pyramidal environment with two short Br=O bonds
and an angled Br-0-Br unit. The two crystallographically
different but chemically identical molecules both have a syn
conformation. Of particular note are the dimers of 1 in the
crystalline solid with a Br . . . Br distance of 2 9 9 3 1 ) pm. This
distance i s even somewhat shorter than the intramolecular
Br . . . Br distance of 305.0(1) pm. The directionality of this
interaction is also indicated by the angles in the -0-Br
Br0- bridge, which are 175.9(2) and 86.4(2)".
A comparison between the structural data of 1 and those
of the compound recently described as Br-O-BrO,'"'
reveals a striking resemblance. The latter was prepared with
the discharge method and characterized by EXAFS as BrOBrO, . The EXAFS method determines fairly accurate bond
lengths only if multiple scattering effects can be excluded o r
if they are properly considered. Moreover, the determination
of the number of neighboring backscatterers (which is generally not very accurate) becomes impossible if perhaps polymorphic products o r even product mixtures are investigated.
A comparison of the Raman spectra also fails to decide if we
have identical or different products. If we restrict ourselves
to the prominent bands above 400cm-'. 1 absorbs at 449,
588. and 849 c m - ' . The postulated r'I1
BrOBrO, absorbs at
453, 582. and 842cm-'. If it is assumed that the local C,,
symmetry of the BrO, part of the molecule dominates the
Raman spectrum, the spectra of the compounds could be
indeed very similar. The detection of BrO, among the hydrolysis products is only meaningful for a uniform product.
The existence of BrOBrO, is therefore questionable.
None of our experiments resulted in a product with a
prominent Raman band at G = 205 cm - I . Theoccurrenceof
this band had been the main argument for the existence of a
bromine oxide formulated as O,Br-BrO,, which should
now be regarded as a totally hypothetical
For the colorless residual bromine oxide, which precipitates on dissolution in CH,CI,, we have as yet not found a
suitable solvent. Its Raman spectrum shows it to be a new
compound, and it seems to be more strongly oxidized, since
the colorless-residue/Br,O, ratio increases with increasing
ozonization time. Its lack of coloration excludes the presence
of a hypobromite group. We refrain from speculating about
i t s structure a t this point.[191At any rate, if Br-0-BrO, 1 is
the first traceable product during ozonization, it is fascinating to think that it might have been formed by a bimolecular
reaction Br, + 0, + BrzO,.
Received: June 5. 1993 [Z61261E]
German version: Anpew. Chew. 1993. /05. I734
H. Davy, Pliilos. li-uns. 1811. 155.
H. S. P. Miiller. H. Willner, Inorg Chem. 1992. 31. 2527 2534.
K . M. Tobias. M. Jansen. Z. Anorg. ANp. Chen?. 1987, 550. 16 26.
A. Simon. H. Borrmann, Anyew. Chmi. 1988. (00. 1386- 138%: Aiigcw.
Cherii. / i i / . Ed. ERR/.1988, 27, 1339 1341.
A. Rehr. M. Jansen. lnorg. Cheiii. 1 9 2 . 31. 4740-4742
C. Campbell. J. P. M. Jones. J. J. Turner. J. C ' h c r i i . Socc Clioii. Coiiiinitn.
1968. 888-889.
W. Levason. J. S. Ogden. M. D. Spicer. N. A. Young. J. Am. U i c v i i . .So..
1990. 112, 1019-1022.
R. Schwarz, M. Schmeisser, Cizeiii. Bw. 1937. 70. 1163- 1166.
M. Schmeisser, K. Joerger, Angi,a.. C/iwii. 1959. 71. 523-~524.
J.-L. Pascal. J. Potier, J. C/icwi. Soc. Cheiii. Cwiiiinin. 1973, 446- 447.
T. R. Gilson, W. Levason. J. S. Ogden. M . D. Spicer. N . A. Young. J. A m .
Cheiii. Soc. 1992. f 14, 5469 - 5470.
D . D. DesMarteau, Inorg. Cliein. 1968, 7. 434-437.
K. Seppelt. Chew. Em. 1973, 160, 157 -164.
B. Piilter. D. Lentz. H. Pritrkow, K. Seppel~,A n p r . U i i w 1981. Y3,
1095-1096: Angew. Cliem. / n t . Ed. Engl. 1981. 20. 1036 1037.
M. Schmeisser. L. Taglinger. Chrvii. Bw. 1961. Y4. 1533 -1539.
C. J. Schack. K. 0 . Christe. R. D. Wilson. Iiiorg. Chain. 1971. 10. 1078
C. J. Schack. K. 0. Christe. Inorg. Cheni. 1974. 13, 2378 2381
W. Breuer. H. J. Frohn. Z. Anorg. Allg. Chem. 1993. 619. 209 214.
M Schmeisser. K . Brindle, Arb. h o r g . Ciiern. Rudiochein. 1963.5.41 89.
A summary ofearher work on ( B r 2 0 $ ) >(Br308)l
and ( B r 0 3 ) \ .None of
these bromine oxides is characterized unambiguously.
Double Lewis Acid Activation in Phosphate
Diester Cleavage""
By Mark Wall, Rosemary C. Hynes, and Jik Chin*
It has recently been shown that a number of important
enzymes that hydrolyze phosphate diesters are activated by
two metal ions. They include 3'-5' exonuclease from DNA
polymerase'll as well as RNase H from HIV reverse transcriptase.['] In order to investigate the cooperativity between
adjacent metal ions for cleaving phosphate diesters, we compared the reactivities of a simple mononuclear and a simple
dinuclear copper (11) complex, using 2-[bis(2-benzimidazolylmethyl)aminomethyl]-4,6-dimethylphenol(HL-1) and 2,6bis[bis( 2-benzimidazolylmethyl)aminomethyl]-4-methylpheno1 (HL-2), which are mono- and dinucleating ligands
respectively (Fig. 1).[31 Here we report on the reactivity of the
Prof. J. Chin, M. Wall, D r R.C. Hynes
Department of Chemistry. McGill University
X01 Sherbrooke Street West. Montreal. Quebec H3A 2K6 (Canada)
Telefax: Int. code + (514)398-3797
Financial support was provided by the National Science and Engineering
Council of Canada and the US Army Research Office.
HL 1
- 0-P
(50 yM) catalyzed by 1 or 2 (1 mM) at 25 "C and pH 7 are
1 0 - s s - l and 2.1 x 10-3s-1, respectively. The dinuclear 2 cleaves HPNP by intramolecular transesterification
rather than by oxidation. The products of the cleavage of
HPNP catalyzed by 2, as detected by 'H and 31PNMR, are
p-nitrophenol and the cyclic phosphate.
To gain some insight into the mechanistic role of the dinuclear complex in cleaving HPNP we obtained a crystal
structure of dibenzyl phosphate (DBP) coordinated to the
copper complex 3.18] The crystal structure reveals that both
oxygen atoms of the phosphate diester are coordinated to
metal centers of the dinuclear complex to form a bridged
structure (Fig. 2). The distance between the two metal centers in 3 (3.67 A) is comparable to that in 3'-5' exonuclease
(3.8 A) and HIV RNase H (4 A). We propose that the key to
the reactivity of 2 for cleaving HPNP is double Lewis acid
activation of the phosphate diester (Fig. 3). Double Lewis
HL 2
' O Y - C H ,
Fig. 1. Structures of HL-I, HL-2, and HPNP.
mononuclear copper (11) complex 1 and the dinuclear copper
complex 2 for cleaving 2-hydroxypropyl-p-nitrophenylphosphate (HPNP).
[(L-l)CuCl] 1
[(L-2)CU2C1,1CI 2
There is considerable interest in developing catalysts that
hydrolyze RNA. Many artificial enzymes that hydrolyze
RNA or simple RNA models (e.g. HPNP) have been reported to date. They include nonmetallic compounds,141as well
as mononuclear transition metal['] complexes and Ianthanide complexes.16]In nature there are many DNases and
RNases that are activated by two metal ions. Crystal structures reveal that both 3'-5' exonuclease"] and RNase H from
HIV reverse transcriptasel21 contain two metal ions at the
active site. There is evidence that the Tetrahymena ribozyme
is also activated by two metal ions.171Site-directed mutagenesis may shed some light into the role of each metal ion in the
enzymes. However, it would be easier to evaluate whether
two metals could be better than one as catalysts in simple
chemical systems rather than in complex biological systems.
Interestingly, 2 is more reactive than 1 for cleaving HPNP.
The pseudo first-order rate constants for cleavage of HPNP
Fig. 3. Proposal for the mechanism
of double Lewis acid activation for
HPNP cleavage.
acid activation should be particularly effective for cleaving
phosphate diesters bound to a nucleophile (for instance,
RNA or HPNP).I9I Single Lewis acid activation in combination with intramolecular metal hydroxide activation has
been shown to be effective for hydrolyzing phosphate diesters not bound to a nucleophile (dimethyl phosphate,
bis(p-nitrophenyl)phosphate).["] Intramolecular metal-hydroxide activation should not provide much rate-acceleration for cleaving phosphate diesters that are already bound
to a nucleophile.
Over the years, many elegant dinuclear metal complexes
with bridging carboxylates or phosphates have been synthesized as spectroscopic models for dimetallic enzymes." In
contrast, functional models of dimetallic enzymes are scarce.
Dinuclear 2 is not only more reactive for cleaving HPNP
than mononuclear 1, but also significantly more reactive
than previously reported nonmetallic catalysts,[4e1and than
mononuclear transition metal c ~ m p l e x e sand
~ ~ ~lanthanide
E-xperimental Procedure
Fig. 2. View of cation in 3 (ORTEP ell~psoidsat the 50% probability level).
Selected bond lengths [A] and angles["]: Cul -Cu2 3.670(4), 0 2 - 0 3 2.496(18);
N2 - Cul -N4 152.8(6), N7-Cu2- N9 91. I .
VerlagsgeseNschaf~mbH, 0-69451 Wernherm, 1993
Compound 3 wds prepared by adding sodium dibenzyl phosphate (10 pmol) to
an ethanolic solution of HL-2 (10 ymol) and Cu(CIO,), (20 pmol). The crude
product was recrystallized from ethanol by slow evaporation to yield thin
greenish plates.
The cleavage of the barium(n) salt of HPNP was followed by monitoring the
increase in the visible absorbance at 400 nrn caused by release ofthey-nitrophenolate ion. In a typical kinetic expenment, 5 mL of a 0.01 M stock solution of
HPNP in water was added to 1 mL of a solution of 1 or 2 (0.5 to 1 mM) at 25 "C
and pH 7.0. The rate constants were obtained by fitting the first three half-lives
of the reaction to a first-order rate low (correlation coefficient > 0.996). Each
kinetic run was reproducible to within 3% error. The pH of the reaction solution did not change appreciably during the course of the hydrolysis as a result
of the buffering effect of the metal complex solution. In water, the coordinated
0570-0833/93/1iil-i634$ iO.OO+.ZSjO
Angen. Chem. In1 Ed. Engl. 1993, 32, N o ii
chloride atoms are replaced by solvent molecules. Potentiometric titration reveals that the plc, values of the two bound water molecules in [(L-2)Cu2(H,0)J3+ are 6.7 and 7.2. The pK, value of the bound water molecule in
[(L-l)Cu(H20)]+is 6.6.
catalytic cycle of iron-containing heme peroxidase~.'~]
Notably all structurally characterized iron(1v) model complexes to
date have the t:g low-spin configuration with a triplet ground
state ( S = 1 ) regardless of the coordination number at the
iron(iv) center (five or six).'' '1
Inspired by the work of Gerbeleu et al. and Leovac
who showed that the trianionic pentane-2,4-dionebis(S-alkylisothiosemicarbazonate), a porphyrin-like, fourcoordinate ligand L3-, can form stable square-pyramidal
iron(1v) complexes [Fe"(L")X]
(X = Cl, Br, I, NCO,
NCSC3"])and [(Fe1vL)2(p-O)],13b1
we determined the crystal
structure of the S-methyl derivative [Fe'"(L")I]
Scheme 1 and Fig. 1, top). The structure is very similar to the
Received: June 23, 1993 [Z 6160 IE]
German version: Angew. Chem. 1993, 105. 1696
111 L. S. Beese. T. A. Steitz. EMBO J. 1991, 10, 25.
[2] J. F. Davies. 2. Hostomska, Z. Hostomsky. S. R. Jordan, D. A. Mathews,
Scienw 1991. 252, 88.
[3] P. B. Hilde, D. W Stephan, Inorg. Chem. 1987, 26, 749.
[4] a ) J. Smith, K. Ariga. E. V. Anslyn. J. Am. Chem. SOF.1993,115.362; b) R.
Breslow. M. Labelle, ihid. 1986, 108, 2655; c) B. Barbier, A. Brack, ihrd.
1992, 114. 351 1; d) M. W. Gobel, J. W. Bats, G. Diirner, Angen. Chem.
1992, 104, 21 7; Angrw. Chrm. 1111.Ed. Engl. 1992, 31, 207; e) V. Jubian,
R. P. Dixon, A. Hamilton, J. Am. Chem. Soc. 1992. 114, 1120.
[ 5 ] a ) J Chin. Aec. Chem. Res. 1991. 25, 145; b) M. K. Stern, J. K. Bashkin.
E. D. Sall. J. Am. Chem. Soc. 1990, 112, 5357; c) W. R. Farkas, Biorhim.
Bmp/rjs. A ~ I U1968. 155, 401 ; d) M. Sundaralingam, J. R. Rubin, J. F.
Cannon, In[. J. Quuntutn Chrm. Quuntum Biol. Symp. 1984, 11, 355; e) Y.
Matsumoto, M. Komiyama. J. Chem. Soc. Chem. Commun. 1990, 1050;
f ) .1. J. Butzow. G. L. Eichhorn, Biopol.vmers 1965, 3, 95. g) R. Breslow,
D. L. Huang, E. Anslyn. Proc. N u f l . Acad. Sci. U S A 1989, 86, 1746.
[6] a ) G. L. Eichhorn, J. J. Butzow. Biopolymers 1965,3, 79; b) J. R. Morrow,
L. A. Buttrey, V. M . Sheiton, K. A. Berback, J. Am. Chem. Sou. 1992,114,
1903; c) R. Breslow, D. L. Huang, Proc. Nut/. Acud. Sc;. USA 1991, 88,
4080. d) J. R. Morrow. L. A. Buttrey, K. A. Berback, Inorg. Chem. 1992,
31. 16.
[7] T. Cech (University of Colorado). private communication.
[ S ] Crystal structural data of 3: triclinic, Pi. u =14.402(3), b = 15.635(3).
c=15.634(3)A. a = 94.819(17). /1=96.546(16), y=117.213(12)', V =
3073.3(10) A3. 2 = 2; 6681 measured reflections, 2931 with I > 2.5 o(/),
322 refined parameters. R = 0.089. Futher details of the crystal structure
investigation may be obtained from the Fachinformationszentrum Karlsruhe. Gesellschaft fur wissenschaftlich-technische Information mbH,
D-76344 Eggenstein-Leopoldshafen (FRG), on quoting the depository
number CSD-57635, the names of the authors, and the journal citation.
[9] The difference in the reactivlty of 1 and 2 may also be in part due to the
difference in the equilibrium constant for coordination of the substrate to
the catalysts.
[lo] a ) J H. Kim. J. Chin, J. Am. Chon. Soc. 1992,114,9792;b) B. K. Takasaki.
J. H. Kim, E. Rubin, J. Chin, ihid. 1993,115, 1 1 5 7 ; ~J.) H. Kim, J. Britten,
J . Chin. ihid. 1993, 115, 3618; d) J. Chin, M. Banaszczyk, V. Jubian, X.
Zou. ihid. 1989. 111. 186.
[ l l ] a) K . Schepers, B. Bremer. B. Krebs, G. Henkel, E. Althaus, B. Mosel, W.
Muller-Warmuth. Angew. Chem. 1990, 102, 582; Angeii.. Chem. Int. Ed.
EngI. 1990, 29. 531. b) S. Uhlenbrock, B. Krebs ;hid. 1992, 104, 1631 and
1992.31. 1647. c) M. Suzuki, H. Kanatomi. I. Murase. Chem. Letr. 1983,
185: d) W. H. Armstrong, A. Spool, G. C. Papaefthymiou, R. B. Frankel,
S. 1. Lippard, J. Am. Chem. Soc. 1984, 106,4632.
( n = 0)
H , C - b
, - N a
[LFeXJ Clod)
Scheme 1. Synthesized square-pyramidal (a) and octahedral (b) iron complexes 1-8.
How "Innocent" Are Pentane-2,4-dionebis(S-alkylisothiosemicarbazonato) Ligands in
Biomimetic Fe" and Fe'" Complexes?**
By Ulrich KnoJ Thomas Weyhermiiller, Thomas Wolter,
Karl Wieghardt,* Eckhard Bill, Christian Butzlaff,
and Alfred X. Trautwein
In recent years a few square-pyramidal and octahedral
ironfrv) complexes have been isolated and structurally characterized." - 3 1 Complexes of this type have been studied in
detail, as compounds with iron in the + I V oxidation state
have been shown by spectroscopy to be intermediates in the
[*] Prof Dr. K . Wieghdrdt, DipLChem. U. Knof,
Dipl.-Chem. T, Weyhermuller. Dipl.-Chem. T. Wolter
Lehrstuhl fur Anorganische Chemie I der UniversitHt
Postfaach 102 148, D-44780 Bochum (FRG)
Telefax: Int. code + (234)7094-201
Dr. E. Bill. Dip1 -Phys. C. Butzlaff, Prof. Dr. A. X. Trautwein
Institut fur Physik der Medizinischen UniversitHt
Ratzeburger Allee 160, D-23538 Liibeck (FRG)
This work was funded by the Fonds der Chemischen Industrie and the
Deutsche Forschungsgemeinschaft.
Angeic.. Chm~.In,. Ed. End. 1993, 32, No. 11
analogous S-ethyl complex.[3a3'1 The iodide ion in 1 was then
exchanged for the biomimetic ligands, thiophenolate and
N-methylimidazole, as well as 2,4,6-trichlorophenolateand
triphenylphosphane, to form 2-5 (Scheme 1). The new fivecoordinate complexes 2-5 were isolated as analytically pure
species; as expected they have an S = 1 ground state (see
Table 1).
We then noticed that the reaction of [(Fe'VL),(p-O)][3b1in
CHCI, with a large excess of PPh, or N-methylimidazole
gave the octahedral complexes 6 and 7 after the addition of
some aqueous HClO, [Eq. (a)]. Treatment of 1 with KCN in
[(LFe'v)z(p-O)]+ 4 X
+ 2H'
6 : X = PPh,
7:X = CH,-C,H,N,
+ H,O
(in CH,CI,)
a two-phase CH,Cl,/H,O mixture, followed by addition of
[AsPhJCl, gave black crystals of 8, the structure of which
has been determined by X-ray crystallography (Fig. 1 botThe complexes 6 and 7 can also be obtained from solutions
of 4 and 5 in CH2Cl, with an excess of PPh, or N-methylim-
VerlugsgesellschaftmbH, 0-69451 Weinheim, 1993
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acid, diesters, cleavage, phosphate, activation, double, lewis
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