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En Route to Synthetic Phosphodiesterases Supramolecular Phosphoryl-Transfer Mediated by AmidiniumЦPhosphate Contact Ion-Pairs.

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[7] J. P. Collman, N. W. Hoffman, D. E. Morris, J Am. Chem. Soc. 1969, 91.
5659: K. R. Grundy, C . A. Reed, W. R. Roper, Chem. Commun. 1970,
1501; G. La Monica, M. Freni, S. Cenini, J Organomel. Chrm. 1974. 7f.
57; K. Wieghardt, U. Quilitsch, Z . Nuturjorsch. B. 1981, 36. 683.
[8] D. Sellmann, G. Pohlmann, F. Knoch, M. Moll, Z . Naturfrrsch. B. 1989,
44, 312.
[9] R. Nast, I. Foppl, Z . Anorg. Allg. Chem. 1950,263,310;G. Stedman, Adv.
Inorg. Chem. Rudiochem. 1979, 22, 113: K. Wieghardt, Adv. Inorg.
Bioinorg. Mech. 1984, 3, 213.
[lo] F. Feigel, V. Anger, Spot Tests in Inorganic Chemistry. Elsevier, New York,
1972, p. 343.
Scheme 1. Reduction of NO on the complex fragment [Mo(NO)('S,')];
exc = excess.
Our results show that in the reduction of NO to NH,OH
at the [Mo(NO)('S,')J fragment, intermediates may be obtained in preparative amounts and completely characterized,
and that the enzymatic reduction of NO to NH,OH should
be favored at coordinatively flexible and redox-active
molybdenum centers in sulfur-dominated coordination
Experimental Procedure
All procedures were carried out under N, and with dry, N,-saturated solvents.
2, NH,OH: A yellow suspension of 1 . THF (1.035g. 1.92mmol) in MeOH
(65 mL) was cooled to 0" and HCI gas was bubbled through the mixture for
15 min. The color changed immediately to red-violet. The suspension was
stirred for 1.5 h at room temperature before N, gas was bubbled through in
order to remove dissolved HCI. Complex 2 was filtered off as a dark-brown
powder. washed with MeOH ( S O mL) and Et,O (20 mL), and recrystallized
from boiling THE 840 mg (93%) black-violet crystals. IR (KBr): B[cm-'] =
1670 (NO); 14N NMR (CD,CI,) : 6 = 44 (NO); FD/EI-MS: m / z 471 (Mf).
Correct elemental analysis.
The filtrate of the reaction mixture was concentrated to dryness. Extraction of
the residue with 5 m L of H,O or D,O provided a mixture of the salts
[NH,OH]CI, [N,H,]CI, and NH,CI. which were characterized by their IR,
mass. and I4N NMR spectra. I4N NMR (D,O): 6 = - 295.5 ([NH,OH]CI),
-329.0 ([N,H,]CI), --355.4 (NH4CI). [NH,OH]CI in the aqueous extract was
also identified by its reaction with a solution of Fe"'/HCHO.[lO] Relative yields
(estimated from NMR spectra): [NH,OH]CI 68, [N,H,]CI 29. and NH,CI 3 %.
3 from 2: N O gas was bubbled through a suspension of 2 (745 mg, 1.59 mmol)
and Zn (52 mg, 0.80 mmol) in THF ( S O mL) for about 1 h until the color of the
suspension had changed from violet to orange-brown. If no change in color
occurred, some fresh Zn powder was added. The reaction mixture was then
filtered. the filtrate evaporated to dryness, the residue taken up in CH,CI,
(30 mL), and 3 precipitated by the addition of Et,O (70 mL). Yield 220 mg
(30%); IR (THF): C[cm-'] = 1770. 1680 (NO); IR (KBr): d[cm-'] = 1760,
1665 (NO); FD/El-MS: m / z 464 ( M ' ) .
Received: September 23, 1991 [Z4925 IE]
German version: Angew. Chem. 1992, 104, 200
CAS Registry numbers:
I , 11607747-3. 2. 121230-37-3; 3, 97775-39-8; [NH,OH]CI, 5470-11-1;
[N,H,]CI, 2644-70-4: NH,OH, 7803-49-8; NO, 10102-43-9; nitrate reductase,
901 303-0: nitrite reductase, 9080-03-9.
[l] M. N. Hughes. The Inorganic Chemi.ytry of Biological Processes, 2nd ed.,
Wiley, New York. 1981, p. 188ff.
[2] M. W. W. Adams. L. E. Mortenson in Meralfonsin Bioiogy, Vol. 7, Molybdenum Er7:yme.r (Ed.: T. G. Spiro). Wiley, New York, 1985, p. 519.
[3] R. J. Lancaster, J. M. Vega, H. Kamin, N. R. Orme-Johnson, W. H. OrmeJohnson. R. J. Krueger. L. M. Siegel, J. Biol. Chem. 1979,254,1268: D. W.
Feng, M. D. Ryan, Inorg. Chem. 1987, 26, 2480.
[4] M. Losada, J Mol. Catal. 1975,1,245;H. Scheer in The Porphyrins, Vol. I1
(Ed.: D. Dolphin), Academic Press, New York, 1979,Chapter 1; C. Costa,
J. J. G. Moura, I. Moura, M. Y Liu. H. D. Peck, Jr., J. LeGall, Y. Wang,
B. H. Huynh. J. Biol. Chem. 1990, 265, 14382; A. J. Pierik, W. R. Hagen,
Eur. J. Biochem. 1991, 195, 505.
[ S ] M. H. Barley, K. Takeuchi, T. J. Meyer, J. A m . Chem. Sac. 1986, fU8,5876;
F. T. Bonner. K. A. Pearsall, Inorg. Chem. 1982, 21, 1973: 0. Kotaro, I.
Hiroshi. J. Chenz. Soc. F a r a d q Trans. 1984.80.2243.
161 D. Selimann, B. Seubert, M. Moll, F. Knoch, Angew. Chem. 1988, 100,
1221: Angew. Chcm. Int. Ed. Engl. 1988. 27, 1164; D. Sellmann, J.
Organomel. Chem. 1989, 372, 99: D. Sellmann, B. Seubert, F. Knoch. M.
Moll, Z Nolurforsch. B 1991, 46, 1449.
Angew. Chem. h r . Ed. Engl. 31 (1992) No. 2
En Route to Synthetic Phosphodiesterases:
Supramolecular Phosphoryl-Transfer Mediated by
Amidinium-Phosphate Contact Ion-Pairs**
By Michael H! Gobel,* Jan H! Bats, and Gerd Diirner
Dedicated to Professor Gerhard Quinkert on the occasion
of his 65th birthday
Amidinium and guanidinium ions associate with carboxylates and phosphates forming hydrogen-bonded contact ionpairs with well-defined structures. In the crystalline state['*21
the cation and the O=P-0 fragment are arranged almost in
a coplanar fashion with symmetrical N-0 distances (ca.
2.9 A). The stability of the ion pairs in solution is dependent
on the polarity of the solvent and its ability to form hydrogen
bonds. Thus, in water the ion-pair stability is
however, in aprotic media association constants up to
I .4x 10' M-' have been recorded.12'
Contact ion-pairs involving arginine side-chains play an
important role in biochemi~try.[~.~I
In the active site of
staphylococcal nuclease, for instance, the phosphodiester to
be cleaved interacts with two arginine cations; because of
their positive charges these residues not only bind the substrate but also facilitate the nucleophilic attack of
electrophilic catalysis.
Inspired by this example we are trying to design simple
"synthetic phosphodiesterases"I81 on the basis of amidinium-phosphate ion-pair complexes (Scheme 1). As a first
step we studied the reaction of amidinium alcohol 1['I with
2 to give 4. This reaction proceeds via ion pair 3 and is
markedly faster than the control reaction of 2 with 5.
On addition of associating anions to 1 one observes a
concentration-dependent downfield shift of the H NMR
- -
0 A o
A 1
Scheme 1. Principle of supramolecular transesterification within an ion-pair
[*] Dr. M. W. Gobel, Dr. J. W. Bats, Dr. G. Durner
Institut fur Organische Chemie der Universitat
Niederurseler Hang, D-W-6000 Frankfurt am Main 50 (FRG)
['*I This research was supported by the Fonds der Chemischen Industrie, the
Deutsche Forschungsgemeinschaft (Go 545/1-1). and the Bundesministerium fur Forschung und Technologie. M. G. thanks Prof. Dr. G.
Quinkert for his generous support.
mhH, W-6940 Weinhcim, 1992
U57U-U833/92/0202-0207$3.50+ ,2510
signal of those amidinium hydrogens parallel to the biaryl
axis ("axial"). Thus, the association constant K , of ion pair
3 could be determined by NMR titration of 1 with the tetramethylguanidinium (TMG+)salt 2. In [D,]DMF the value of K, is 200( f 30) M - ' but is reduced to only 14 M - ' in
[DJDMSO (both values 30 "). In contrast, the substantial
downfield shift of the NH,, signal of product 4 is independent of concentration. Compound 4 is thus assumed to be an
inner ion-pair in solution.
the naphthalene frame is twisted. The torsion angle between
the phenyl and naphthalene planes is 58". In the barely disturbed ion-pair substructure, the unsubstituted oxygen centers of the phosphate group form hydrogen bonds with the
cation 2.86 and 2.92 8, in length.
Due to ring strain 2 is one of the most reactive phosphodiesters;" 'I yet in its reaction with phenylethanol5 and diisopropylethylamine in DMF, 2 opens very slowly to 6
( k , = 2.2( f 0.2) x lo-' M - min- ', 30°, 0.25 M base, analysis by HPLC). The reaction of 2 with amidinium alcohol 1
(30", 0.25 M base in DMF) is much faster and follows a
Michaelis-Menten-type saturation kinetics when the phosphate concentration exceeds the amidinium concentration
(Fig. 2). This demonstrates that the phosphorylation of 1 is
not an intermolecular but rather a supramolecular (quasiintramolecular) process within ion pair 3. Accordingly, the
saturation curve (Fig. 2) can be predicted satisfactorily from
the association constant K,. If 1 is employed as an acetate
instead of a perchlorate-the acetate counterion has a higher
affinity to the amidinium group than the cyclophosphate in
2-the reaction is strongly inhibited as expected.
\ k.?'
c(l I
Fig. 2. Rate of the phosphorylation of 1 versus the concentration relationship
The crystal structure analysis of 4 provides further de(Fig. 1). Due to the close proximity of the phenyl and
amidinium groups these substituents are forced apart and
Fig. 1. Crystal structure of 4 [lo].
Verlagsgesellschafi mbH. W-6940 Weinheim, 1992
The first-order rate constant measured at complete saturation for the quasi-intramolecular reaction of 3 was determined to be 9.9(+ 0.4) x 1OP6 min-'. To allow a comparison with k , of the control reaction the product
K,k, = 1.98 x
M - 'min- ' can be used, which describes
the second-order rate constant for the reaction of 1 and 2 at
high dilution. K,k, corresponds to the expression k,,Ki
well known in enzyme kinetics. The data show that 1 has a
9000-fold rate advantage over uncharged alcohol 5 . The effective molarity of the hydroxy group of 3 as expressed by
k,k;' is 45 M .
The substantial acceleration of the phosphorylation reaction is due not only to the spatial proximity of the reacting
groups in complex 3 but also to electrophilic activation of the
phosphodiester by the coordinating amidinium ion (see
staphylococcal nuclease). This coordination accelerates both
the conversion of 3 to 4 and the intermolecular reaction of 3
with phenylethanol 5 and is comparable to electrophilic
catalysis by coordinated metal-ions. As a result, the phosphorylation of 5 in the presence of amidinium salt 1 again
shows a saturation effect when the phosphate concentration
exceeds the amidinium concentration. For the reaction of 5
with ion pair 3 the constant k; is roughly 25 times greater
than the constant k , for the free cyclophosphate 2["] (each
measured at 30 "C, 0.25 M base in DMF). The addition of
0870-0833/92/0202-0208$3.80+ ,2810
Angew. Chem. In!. Ed. Engl. 31 (1992) No. 2
one equivalent (relative to 2) of bis(guanidinium) salt 7 accelerates the control reaction even more than 2000-fold. In the
next step on the way to “synthetic phosphodiesterases” ke-
A New Synthesis for Lmidazolo- and
Pyrrolophanes by 13 + 2JCycloadditionwith
Azaallenyl Radical Cations **
By Felix Miiller and Jochen Mattay*
F 3 c yOH
tone hydrates of type 8 will be used for the reversible binding
of H,O.
Received: September 30, 1992 [Z49421E]
German version: Angew. Chem. 1992, 104, 217
Since the development of supramolecular chemistry the
interest in cyclophanes and heterocyclophanes has grown
steadily because of their possible use as receptor models and
their application in phase-transfer catalysis.[‘] Our recently
published method, the [3 + 2]cycloaddition of azirines with
olefins and imines by means of Photoinduced Electron
Transfer (PET),’21provides a new approach for the synthesis
of heterocyclophanes.
The reaction is conducted under PET reaction conditions :[31 the electron acceptor 1,4-naphthalenedicarbonitrile
(DCN) is excited by irradiation with light 1 = 350 nm in the
presence of azirine 1, leading to the DCN radical anion and
a reactive azirine radical cation. This latter species opens to
the linear 2-azaallenyl radical cation 2.t41In a two-step process 2 adds to double bonds and their equivalents. Addition
of 2 to the C=N bond of an imine under these conditions
leads via a dihydroimidazole to an imidazole.[*.51 Bicyclic
azirines 1a-c react with imines 3 to give [n](2,4)imidazolophanes (Scheme 1, Table 1).
CAS Registry numbers:
1, 137966-19-9; 2, 137966-20-2; 3, 137966-22-4;4, 137966-24-6;4 . CH,OH,
137966-25-7; 5, 60-12-8; 6, 137966-23-5.
[l] F. A. Cotton, V. W Day, E. E. Hazen, Jr., S . Larsen, J. Am. Chem. SOC.
1973. 95.4834-4840.
[2] G. Miiller, J. Riede, F. P. Schmidtchen, Angew. Chem. 1988, 100, 15741575; Angew. Chem. Int. Ed. Engl. 1988,27, 1516.
[3] B. Springs, P. Haake, Bioorg. Chem. 1977,6, 181-190.
[4] J. F. Riordan, Mol. Cell. Eiochem. 1979, 26, 71-92.
[5] B. J. Calnan, B. Tidor, S. Biancalana, D. Hudson, A. D. Frankel, Science
1991,252, 1167-1171.
[6] F. A. Cotton, E. E. Hazen, Jr., M. J. Legg, PFUC.Null. Acud. Sci. USA
1979, 76, 2551 -2555.
(71 J. Aqvist, A. Warshel, Biochemislrj 1989, 28, 4680-4689.
(81 ATP hydrolysis mediated by macrocyclic polyammonium compounds:
a) M. W. Hosseini, J.-M. Lehn, L. Maggiora, K. Bowman Mertes, M. P.
Mertes, J. Am. Chem. Soe. 1987, 109, 537-544; cleavage of phosphodiesters: b) A. C. Hengge, W. W. Cleland. J. Org. Chem. 1991, 56, 19721974; (see also [Sfl); metal-catalyzed: c) E M. Menger, L. H. Gan, E.
Johnson. D. H. Durst, J. Am. Chem. Soc. 1987, 109, 2800-2803; d) J. R.
Morrow. W. C . Trogler, Inorg. Chem. 1988,27,3387-3394; e) J. Chin, Acc.
Chem. Res. 1991,24,145-152; RNA hydrolysis: f ) R. Breslow, E. Anslyn,
D.-L. Huang, Tciruhedron 1991,47, 2365-2376; g) B. Barbier, A. Brack,
J Am. Chem. SOC.1988, 110, 6880-6882; h)A. S. Modak, J. K. Gard,
M. C . Merriman, K. A. Winkeler, J. K. Bashkin, M. K. Stern, ibid. 1991,
113, 283-291; i) K. Yoshinari, K. Yamazaki, M. Komiyamd, ibid. 1991,
113, 5899 -5901 ; DNA hydrolysis: j) L. A. Basile, A. L. Raphael, J. K.
Barton, ihid. 1987, 109, 7550-7551.
[9] We will report the synthesis of 1 in a later publication. All new compounds
were characterized by the standard spectroscopic methods and provided
correct elemental analyses.
[lo] X-ray structure analysis of 4: Enraf-Nonius-CAD4 diffractometer, Cu,,
radiation, 20 = 124‘, empirical absorption correction based on Y-scans;
structure determination with direct methods with SHELX-86; the hydrogen atoms were not refined; the positions of the hydrogens a t 0 and N
were obtained from a difference Fourier synthesis: C,,H,,N,O,P .
CH,OH, orthorhombic, space group P2,2,2,, u =7.760(2), b =
11.7190(8), c = 27.577(2) A,
V = 2507.9(9) A3, Z = 4, P,,~, =
1.310 gcm-’; of 3946 independent reflections 3906 with I 0 were used;
R = 0.046, R, = 0.045. The residual density was less than 0.24 e k 3 . Further details of the crystal structure investigation may be obtained from the
Fachinformationszentrum Karlsruhe, Gesellschaft fur wissenschaftlichtechnische Information mbH, D-W-7514 Eggenstein-Leopoldshafen 2
(FRG) on quoting the depository number CSD-55686, the names of the
authors, and the journal citation.
(111 a) E. T. Kaiser, K . Kudo, J. Am. Chem. SOC.1967, 89, 6725-6728; b) L.
Atwood, P. Haake, Eioorg. Chem. 1976, 5, 373-382; see also [Sfl.
[I21 A similar effect was observed with guanidinium salts in aqueous solution:
B. Springs, P. Haake, Tetrahedron Lett. 1977, 3223-3226.
Angew. Chern. I n t . Ed. Engl. 31 11992) No. 2
- E a t
Scheme 1. l a , n = 4; I b , n = 5; l c , n
4a-c see Table 1.
= 6;3a, R
= n-propyl;3b, R = phenyl.
Table 1 . Isolated imiddzolophanes.
no reaction
2 Yo
27 Yo
The bridge must comprise at least five methylene units for
the reaction to succeed. Reasonable yields may be obtained
for products with bridges of at least six methylene units and
appropriate substituents next to the N atom, as in 4b. The
[*I Prof. Dr. J. Mattay, Dipl.-Chem. F. Miiller
Organisch-chemisches Institut der Universitgt
OrMansring 23, D-W-4400 Miinster (FRG)
[‘*I Radical Ions and Photochemical Charge-Transfer Phenomena (Series A),
Part 33, and Cycloadditions (Series B), part 37. This work was supported
by the Deutschen Forschungsgemeinschaft, the Fonds der Chemischen
Industrie, and the state of Nordrhein-Westfalen. We also thank Bayer AG,
Philips Bildrohrenwerke AG, and Heraeus AG for generous gifts of chemicals and equipment. - Series A, Part 32: E. Bischof, J. Mattay, J. Photochem. Photohiol. A . 1992,63,249-251; Series B, Part 36: K. Langer, J.
Mattay, A. Heidbreder, M. Moller, Liebigs Ann. Chem. 1992, in press.
Q VCH Verlugsgesellschaft mhH. W-6940 Weinheim. 1992
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synthetic, amidiniumцphosphate, ion, phosphodiesterases, supramolecular, transfer, contact, pairs, phosphorus, route, mediated
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