Structure-reactivity relationship for the cobalt(III) complex-catalysed hydrolysis of adenosine 3′,5′-cyclic monophosphate

Article abstract of DOI:10.1039/a604305d

Hydrolysis of adenosine 3′,5′-cyclic monophosphate (cAMP) by cobalt(III) complexes [Co(N₄XH₂O)₂]³⁺ (N₄: two diamines or one tetraamine) has been systematically studied at pH 7 and 50°C. Both the catalytic activity and the product distribution are highly dependent on the nature of the amine ligand. The relative catalytic activities are cyclen (4000) > trien (500) > (tme)₂ (57) > tren (37) > (tn)₂ (22) > 2,3,2-tet (7) > (en)₂ (1) ? cyclam, cth, dien. The pseudo-first-order rate constant for the cyclen complex (0.05 M) is 1.2 h^-1 (half-life 35 min), corresponding to a 10¹⁰-fold acceleration with respect to the uncatalysed reaction. Of the two P-O linkages in cAMP, the cyclen, the trien and the 2,3,2-tet complexes preferentially cleave the P-O(5′) linkage, whereas the (tme)₂ and the (tn)₂ complexes promote P-O(3′) scission. Adenosine is the main product for hydrolysis by the (tme)₂ complex, whereas adenosine monophosphates as the hydrolysis intermediates are accumulated in the catalysis by the trien complex.

Full text of DOI:10.1039/a604305d

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Structure–reactivity relationship for the cobalt(III) complex-catalysed
hydrolysis of adenosine 3Ј,5Ј-cyclic monophosphate1
Makoto Komiyama,* Jun Sumaoka, Koji Yonezawa, Yoichi Matsumoto and
Morio Yashiro
Department of Chemistry and Biotechnology, Graduate School of Engineering,
the University of Tokyo, Hongo, Tokyo 113, Japan
H ydrolysis of adenosine 3Ј,5Ј-cyclic monophosphate (cAM P) by cobalt(III) complexes [Co(N 4)(H 2O)2]3+
(N 4: two diamines or one tetraamine) has been systematically studied at pH 7 and 50 oC. Both the catalytic
activity and the product distribution are highly dependent on the nature of the amine ligand. The relative
catalytic activities are cyclen (4000) > trien (500) > (tme)2 (57) > tren (37) > (tn)2 (22) > 2,3,2-tet (7) > (en)2
(1) ӷ cyclam, cth, dien. The pseudo-first-order rate constant for the cyclen complex (0.05 M ) is 1.2 hϪ1
(half-life 35 min), corresponding to a 1010-fold acceleration with respect to the uncatalysed reaction. Of the
two P᎐O linkages in cAM P, the cyclen, the trien and the 2,3,2-tet complexes preferentially cleave the
P᎐O(5Ј) linkage, whereas the (tme)2 and the (tn)2 complexes promote P᎐O(3Ј) scission. Adenosine is the
main product for hydrolysis by the (tme)2 complex, whereas adenosine monophosphates as the hydrolysis
intermediates are accumulated in the catalysis by the trien complex.
Introduction
Adenosine 3Ј,5Ј-cyclic monophosphate (cAMP), a second mes-
senger for cell-to-cell communication, is formed from adeno-
sine triphosphate by adenylate cyclase, when cells are activated
by external stimuli.2 The cAMP modulates the activities of
intracellular enzymes, resulting in the regulation of the bioreac-
tions. The response terminates when the cAMP is hydrolysed by
phosphodiesterase. Thus, efficient catalysts for cAMP cleavage
are important in the design of artificial cell-regulating systems
as well as for detailed investigation of the mechanism of
information-transfer in cells.
Previously,3 Chin and Zou reported that cAMP hydrolysis is
greatly (108-fold) accelerated by [Co(trien)(H2O)2]3+. Further-
more, Sargeson et al.4 showed that [Co(tn)2(H2O)2]3+ preferen-
tially cleaves the P–O(3Ј) linkage over the P–O(5Ј) linkage (the
abbreviations of the ligands are presented in Fig. 1). These find-
ings indicated that CoIII complexes have potential in artificial
regulation of cell functions.5,6 Undoubtedly, detailed inform-
ation on the relationship between the structure of the complexes
and their catalytic properties is crucially important.
We report here the results of a systematic study on
cAMP hydrolysis by diaquatetraazacobalt() complexes
[Co(N4)(H2O)2]3+ (N4: two diamines or one tetraamine).
Dependencies of the catalytic activity and product distribution
on the structure of amine ligand (shown in Fig. 1) are quantita-
tively analysed. Factors governing the reactivity and the regio-
selectivity are clarified. Furthermore, a reaction mechanism is
proposed in terms of the kinetic and spectroscopic evidence.
Experimental
Fig. 1 Ligands used in the present study and their abbreviations.
Abbreviations: cyclen, 1,4,7,10-tetraazacyclododecane; trien, triethyl-
enetetramine; tme, 1,1,2,2-tetramethylethylenediamine; tren, tris(2-
aminoethyl)amine; tn: 1,3-diaminopropane; 2,3,2-tet, N,NЈ-bis(2-
aminoethyl)-1,3-diaminopropane; en, ethylenediamine; cyclam,
1,4,8,11-tetraazacyclotetradecane; cth, 7(R),14(R)-5,5,7,12,12,14-
hexamethyl-1,4,8,11-tetraazacyclotetradecane; dien, diethylenetri-
amine.
Materials
1,1,2,2-Tetramethylethylenediamine (tme) 7 and 7(R),14(R)-
5,5,7,12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane
(cth)8 were synthesized as described previously. Other amine
ligands were purchased from Nacalai or Tokyo Kasei Organic
Chemicals. The CoIII complexes [Co(N4)Cl2]+ were prepared
according to the literature.4,5,9–11 Aqueous solutions of EuII for
the pretreatment of HPLC specimens were prepared by treating
acidic solutions of Eu2O3 with zinc metal. Highly purified water
(specific resistance > 18.3 MΩ) was sterilized immediately
before use. Throughout the present study, great care was taken
to avoid contamination by other metal ions and natural
enzymes.
J. Chem. Soc., Perkin Trans. 2, 1997
75

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Table 1 First-order rate constants for the hydrolysis of cAMP by
[Co(N4)(H2O)2]3+ at pH 7 and 50 ЊC as well as the 3ЈA :5ЈA ratios in
the products a
Table 2 First-order rate constants (in 10Ϫ2 Ϫ1) for the hydrolysis
h
of adenosine monophosphates by [Co(trien)(H2O)2]3+ and [Co-
(tme)2(H2O)2]3+ at pH 7 and 50 ЊC
a
b
Ligand
Rate constant/(hϪ1
)
3ЈA :5ЈA ratio
Ligand
3ЈA
5ЈA
cAMP
cyclen
trien
(tme)2
tren
(tn)2
2,3,2-tet
(en)2
cyclam
cth
dien
1.2
5.6
4.5
0.40
1.4
0.13
5.0
—
—
—
—
—
trien
(tme)2
4.2
19
1.1
24
15
1.7
1.5 × 10Ϫ1
1.7 × 10Ϫ2
1.1 × 10Ϫ2
6.6 × 10Ϫ3
2.6 × 10Ϫ3
3.0 × 10Ϫ4
––c
a [CoIII complex] = 5 × 10Ϫ2 and [cAMP]0 = 4 × 10Ϫ4 .
are only 3ЈA, 5ЈA and A, confirming the hydrolytic character
of the scission.
The hydrolysis rate depends strongly on the structure of
amine ligand: cyclen > trien > (tme)2 > tren > (tn)2 > 2,3,2-tet >
(en)2. The hydrolysis rate by the cyclen complex is 4000-fold
greater than that by the (en)2 complex [note that even the (en)2
complex accelerates the hydrolysis by more than 106-fold]. In
contrast, the hydrolysis by the CoIII complexes of cyclam and
cth is too slow to allow the precise determination of the rate
constants. A triamine complex [Co(dien)(H2O)3]3+ also has
poor activity.
––c
––c
None
1.2 × 10Ϫ10d
a [CoIII complex]0 = 5 × 10Ϫ2 and [cAMP]0 = 4 × 10Ϫ4 . b The ratios of
the monophosphates accumulated in the reaction mixtures. c Too small
to be precisely determined. d The value from ref. 3.
Hydrolysis of cAMP
Typical procedures are as follows.5g To an aqueous solution of
[Co(N4)Cl2]+, 1.5 equiv. of NaOH were added. The mixture was
incubated for 20 min, during which the corresponding
[Co(N4)(H2O)2]3+ (existing mostly as [Co(N4)(OH)2]+) was
formed in situ. The pH of the solution was adjusted to a desired
value by use of a small amount of hydrochloric acid.
Hydrolysis of cAMP (from Sigma) was achieved at 50 oC with-
out any additional buffer agents. The coordinated water mol-
ecules of the CoIII complexes (pKa values are ca. 6–8) satis-
factorily kept the pH constant during the reactions (the change
was less than 0.1 pH unit).
Preference of the P᎐O(3Ј) scission vs. the P᎐O(5Ј) scission
The ratio of 3ЈA to 5ЈA in the product is also notably dependent
on the kind of amine ligand, as shown in Table 1. For the
cyclen, the trien, the 2,3,2-tet, and the tren complexes, 3ЈA is the
major product, showing that the P–O(5Ј) bond is preferentially
cleaved over the P–O(3Ј) bond. With the (tme)2 and the (tn)2
complexes, however, the selectivity is reversed and 5ЈA is
formed predominantly.† The 3ЈA :5ЈA ratios for the trien and
the (tn)2 complexes are in reasonable accord with the values
reported by Sargeson et al.‡,4
HPLC analysis of cAMP hydrolysis
Complete hydrolysis or partial hydrolysis.
At an appropriate interval, an aliquot (5 µl) of the reaction
solution was analysed by reversed-phase HPLC [Merck
LiChrospher 18(e) column, 25 cm; eluent, pH 4 buffer contain-
ing acetonitrile (2 vol%), KH2PO4 (50 m), and choline chlor-
ide (20 m) as an ion-pair agent; detection at 258 nm]. Prior to
injection to the system, the specimens were pretreated as fol-
lows.10 First, the CoIII ions therein were reduced to the CoII by
an aqueous 0.2  solution of EuII ion (45 µl). Then a saturated
aqueous solution of KH2PO4 (50 µl) was added. The resultant
mixture was centrifuged to remove the precipitates, and finally
was treated with a pretreatment disk (Tosoh, W-3-2).
Furthermore, the amine ligand strongly affects the relative rates
of the first step (cAMP → 3ЈA,5ЈA) and of the second step
(3ЈA,5ЈA → A) for the cAMP hydrolysis. Thus, the distribu-
tions of the products in the reaction mixtures are significantly
different from each other. When [Co(trien)(H2O)2]3+ was used
as catalyst, 3ЈA and 5ЈA as the intermediates were accumulated
in the reaction mixture. Formation of A was not observed even
after 10 h, where ca. 80 mol% of cAMP was cleaved. The sec-
ond step is catalysed less by the complex. Similar results were
obtained for the cyclen and the 2,3,2-tet complexes.
With the (tme)2 complex, however, cAMP was hydrolysed
straightforwardly to A without considerable accumulation of
3ЈA and 5ЈA. More than 80% of the hydrolysis products was A,
when the conversion of cAMP cleavage was 50 mol%. Still
higher selectivity was obtained by the (en)2 complex: 50 mol%
conversion of cAMP cleavage gave 97% hydrolysis product A.
Hydrolysis by the tren complex was less selective, and consider-
able amounts of 3ЈA, 5ЈA and A were present in the reaction
mixtures.
Table 2 lists the rate constants for the hydrolysis of 3ЈA and
5ЈA to A by the trien and the (tme)2 complexes, which were
determined by use of authentic samples of the adenosine
monophosphates. For the hydrolysis of both 3ЈA and 5ЈA, the
(tme)2 complex has greater catalytic activity than the trien com-
plex. In the cleavage of cAMP to 3ЈA and 5ЈA, however, the
trien complex is more active than the (tme)2 complex, see also
Table 2. These results are consistent with the accumulation of
adenosine monophosphates only with the trien complex. Subtle
changes in the structure of the amine ligand give rise to a dras-
All the hydrolysis products, adenosine 3Ј-monophosphate
(3ЈA), adenosine 5Ј-monophosphate (5ЈA), and adenosine (A),
as well as cAMP, were clearly resolved by HPLC (the retention
times were 10.7, 8.2, 33.1 and 37.1 min, respectively). The sig-
nals were assigned by coinjection with the corresponding
authentic samples. All the cAMP hydrolysis fairly showed
pseudo-first-order kinetics.
Spectroscopy
31P NMR spectra were measured at pD 7 in D2O on a JEOL
EX-270 spectrometer with 85% H3PO4 as an external standard.
The specimens were prepared as described above for the cAMP
hydrolysis experiments, and were immediately subjected to
spectroscopic measurements.
Results and discussion
Catalytic activities of CoIII complexes for cAMP hydrolysis
The catalytic activities of the CoIII complexes for the
hydrolysis of cAMP at pH 7 and 50 oC are listed in Table 1. The
pseudo-first-order rate constant for [Co(cyclen)(H2O)2]3+ (0.05
) is 1.2 hϪ1, corresponding to a half-life of 35 min. Thus, a 1010-
fold acceleration (with respect to the uncatalysed reaction) has
been accomplished (the half-life in the absence of the catalyst is
estimated to be 660 000 years).3 This is, to our knowledge, the
most active CoIII complex for cAMP hydrolysis. The products
† The rate constants for the hydrolysis of 3ЈA and 5ЈA to A by the tme
complex are comparable with each other (see Table 2), and thus the
3ЈA :5ЈA ratio presented in Table 1 satisfactorily reflects the regioselec-
tivity of the scission of the P–O bonds.
‡ The 3ЈA :5ЈA ratio 0.40 for the (tme)2 complex is different from the
value (2) in ref. 4. The reason for the discrepancy is not clear.
76
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Fig. 4 The proposed mechanism for the CoIII-catalysed hydrolysis of
cAMP
coordinating to the trien complex (monodentate coordination
of a phosphate to CoIII complexes causes a downfield shift, in
most cases, of 5–10 ppm).12 By use of the intensities of the
signals, the equilibrium constant for the complex formation
between cAMP and [Co(trien)(H2O)2]3+ was estimated to be
ca. 0.1 dm3 molϪ1.
Fig. 2 Plot of the pseudo-first-order rate constant for the cAMP
hydrolysis vs. the concentration of [Co(trien)(H2O)2]3+ at pH 7 and
50 ЊC: [cAMP]0 = 4 × 10Ϫ4 
Reaction mechanism for the cAMP hydrolysis
The cAMP hydrolysis involves [Co(N4)(OH)(cAMP)]+ com-
plexes, in which a hydroxide ion coordinates to the CoIII ion in
the cis position to the cAMP. In these cis complexes, the hydrox-
ide ion intramolecularly attacks the phosphorus atom of the
cAMP (Fig. 4: a similar mechanism was proposed by Chin et
al.).3 Both the linear increase of the hydrolysis rate with [CoIII
complex]0 (Fig. 2) and the bell-shaped pH–rate constant profile
(Fig. 3) are consistent with the mechanism.§ The equilibrium
constant for the complex formation between cAMP and the
CoIII complex is so small that a saturation phenomenon is not
observed under the conditions employed. The anation step is
sufficiently fast and cannot be rate-limiting.5g,h
The argument is supported by the fact that the cyclen com-
plex, which is rigidly fixed in a cis form,13 is quite active for the
reaction. In contrast, the cyclam complex, which favourably
takes a trans form,14 shows only marginal catalysis (see Table 1).
The cis configuration is required for the proposed mechanism.
The order of the catalytic activities of the CoIII complexes
for cAMP hydrolysis [cyclen > trien > tren > (en)2] coincides
well with that for the hydrolysis of bis(4-nitrophenyl) phos-
phate.5g,h The validity of the proposed mechanism has been fur-
ther confirmed, since the latter reactions proceed via a similar
mechanism involving an intramolecular attack by the metal-
bound hydroxide toward the phosphorus atom.
Fig. 3 The pH–rate constant profile for the [Co(trien)(H2O)2]3+-
catalysed hydrolysis of cAMP at 50 ЊC: [trien complex] = 5 × 10Ϫ2 and
[cAMP]0 = 4 × 10Ϫ4 : the pKa values of the hydration water of the
CoIII complex are 5.9 and 8.1 [ref. 5(e)]
Factors governing the reactivity and the regioselectivity of
CoIII complexes
tic difference in the catalytic activities for the hydrolysis of the
phospho-diesters and -monoesters.
The catalytic activities of the CoIII complexes are primarily
governed by the stability of the four-membered ring intermedi-
ate, formed on intramolecular attack by the metal-bound
hydroxide towards the phosphate (Fig. 4). As proved by Chin
et al. in the hydrolysis of bis(4-nitrophenyl)phosphate,5h the
stability of the four-membered CoIII complex is highly depen-
dent on the amine ligand. The complex becomes more stable as
the bond angle opposite the four-membered ring increases.
Quite significantly and reasonably, the dependence of the
reactivity on the ligand structure for the present cAMP
hydrolysis [cyclen :trien :tren :(en)2 = 4000:500:37:1] is more
marked than that (170:18:3:1) for the hydrolysis of bis(4-
Kinetic analysis of cAMP hydrolysis by [Co(trien)(H2O)2]3+
The rate constant for the cAMP hydrolysis increases linearly
with increasing concentration of [Co(trien)(H2O)2]3+, as
depicted in Fig. 2. Only one CoIII complex participates in the
hydrolysis. The pH–rate constant profile is bell-shaped, giving a
maximum at ca. pH 7 (Fig. 3). It is strongly indicated that
[Co(trien)(H2O)(OH)]2+ is the active species [see eqn. (1): the
pKa values for the dissociation of the coordinated water mol-
ecules in the CoIII complex are 5.9 and 8.1].5e
Ka1
[Co(trien)(H2O)2]3+
Ka2
[
[Co(trien)(H2O)(OH)]2+
[Co(trien)(OH)2]1+ (1)
§ The pH–rate constant profile should be treated, in principle, in terms
of the pKa value of the species [Co(N4)(OH2)(cAMP)]2+, in place of the
value for [Co(N4)(OH2)(OH)]2+. However, the present treatment is rea-
sonably acceptable, since the kinetically determined pKa values for the
CoIII complex-catalysed hydrolysis of diaryl phosphates are almost
identical with the corresponding values determined by potentiometric
titration [ref. 5(h)].
Complex formation between cAMP and [Co(trien)(H2O)2]3+
When [Co(trien)(H2O)2]3+ was mixed with cAMP at pD 7, a new
31P-signal appeared at δ 8.7. The signal of free cAMP was
located at δ 2.1. The new signal is assignable to the cAMP
J. Chem. Soc., Perkin Trans. 2, 1997
77

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nitrophenyl)phosphate. In the cAMP hydrolysis, the four-
membered ring is fusing with the six-membered ring involving
the phosphodiester, which is further fusing with the five-
membered ring of the ribose. Thus, the stabilization of the four-
membered ring, which is otherwise quite unstable, by the amine
ligand should prove still more crucial for the cAMP hydrolysis
to proceed efficiently.
Acknowledgements
Theauthorsthank Professor R.M.Milburn of Boston University
for valuable comments on the HPLC analysis. This work was
partially supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, and Culture, Japan.
References
Of the two P–O bonds in cAMP, the P–O(5Ј) linkage is pref-
erentially cleaved, when the four nitrogen atoms in the ligands
are covalently bound (as in cyclen, trien and 2,3,2-tet). On the
other hand, (N2)2 type ligands [(tme)2 and (tn)2] promote the
P᎐O(3Ј) scission (see Table 1). Presumably, the molecular flex-
ibilities of the CoIII complexes are different from each other,
which in turn affects the efficiency of pseudo-rotation in the
pentacoordinated reaction intermediate.15 In the (tme)2 and the
(tn)2 complexes, the pseudo-rotation takes place vigorously
prior to P–O scission so that the P–O(3Ј) scission involving a
better leaving group predominates. The pKa of the 3Ј-OH of
ribose (ca. 12) is significantly smaller than that of the 5Ј-OH
residue.16 For the cyclen, the trien and the 2,3,2-tet complexes,
however, the pseudo-rotation is less efficient due to the tetra-
coordinating chelation of the ligands. Under these conditions,
the direction of the nucleophilic attack by the CoIII-bound
hydroxide toward the phosphorus atom, at least partially, gov-
erns the regioselectivity.¶
1 Preliminary communication: K. Yonezawa, Y. Matsumoto and
M. Komiyama, Nucleic Acids, Symp. Ser., 1991, 25, 145.
2 H. Dugas and C. Penney, Bioorg. Chem., Springer, New York,
1981.
3 J. Chin and X. Zou, Can. J. Chem., 1987, 65, 1882.
4 R. Wijesekera, P. Hendry and A. M. Sargeson, Aust. J. Chem., 1992,
45, 1187.
5 CoIII complexes are also active for the hydrolysis of various phos-
phate esters: (a) P. R. Norman and R. D. Cornelius, J. Am. Chem.
Soc., 1982, 104, 2356; (b) D. R. Jones, L. F. Lindoy and A. M.
Sargeson, J. Am. Chem. Soc., 1983, 105, 7327; (c) G. Rawji, M.
Hediger and R. M Milburn, Inorg. Chim. Acta, 1983, 79, 247;
(d) D. R. Jones, L. F. Lindoy and A. M. Sargeson, J. Am. Chem.
Soc., 1984, 106, 7807; (e) R. A. Kenley, R. H. Fleming, R. M. Laine,
D. S. Tse and J. S. Winterle, Inorg. Chem., 1984, 23, 1870; (f) R. M.
Milburn, M. Gautem-Basak, R. Tribolet and H. Siegel, J. Am.
Chem. Soc., 1985, 107, 3315; (g) J. Chin and X. Zou, J. Am. Chem.
Soc., 1988, 110, 223; (h) J. Chin, M. B. Banaszczyk, V. Jubian
and X. Zou, J. Am. Chem. Soc., 1989, 111, 186; (i) J. Chin and
M. Banaszczyk, J. Am. Chem. Soc., 1989, 4103; (j) J. H. Kim and
J. Chin, J. Am. Chem. Soc., 1992, 114, 9792 and references therein.
6 Catalytic hydrolysis of cAMP by lanthanide ions was reported: (a)
J. Sumaoka, M. Yashiro and M. Komiyama, J. Chem. Soc., Chem.
Commun., 1992, 1707; (b) J. Sumaoka, S. Miyama and M. Komi-
yama, J. Chem. Soc., Chem. Commun., 1994, 1755.
There is no correlation between the acid properties of the
CoIII-bound water molecules and the catalytic activities of the
complexes; the pKa1 and pKa2 values of the CoIII complexes are
as follows: 5.6 and 8.0 for cyclen;5h 5.9 and 8.1 for trien;5e 4.8
and 8.7 for tme;5e 5.5 and 8.0 for tren;5h 5.6 and 8.1 for tn.5e The
possibility that the catalytic properties are determined by these
acid–base properties is ruled out.
7 R. Sayre, J. Am. Chem. Soc., 1955, 77, 6689.
8 H. Ito, J. Fujita, K. Toriumi and T. Ito, Bull. Chem. Soc. Jpn., 1981,
54, 2988.
In conclusion, both the catalytic activities and the regio-
selectivities of CoIII complexes are markedly dependent on the
structure of amine ligand. Steric factors are predominant. The
present systematic information sheds light on the molecular
design of CoIII complexes useful for the artificial regulation of
cell functions.
9 A. M. Sargeson and G. H. Searle, Inorg. Chem., 1967, 6, 787.
10 F. Tafesse and R. M. Milburn, Inorg. Chim. Acta, 1987, 135, 119.
11 M. Yashiro, M. Komiyama, K. Kuroda, S. Miura, S. Yoshikawa and
S. Yano, Bull. Chem. Soc. Jpn., 1994, 67, 3276.
12 G. P. Haight, Jr., Coord. Chem. Rev., 1987, 79, 293.
13 Y. Iitaka, M. Shina and E. Kimura, Inorg. Chem., 1974, 13, 2886.
14 (a) C. K. Poon and M. L. Tobe, J. Chem. Soc., A, 1968, 1549; (b)
G. A. Melson, Coordination Chemistry of Macrocyclic Compounds,
ed. G. A. Melson, Plenum Press, New York, 1979, 2.
15 F. H. Westheimer, Acc. Chem. Res., 1968, 1, 70.
16 R. M. Izatt, J. H. Rytting, L. D. Hansen and J. J. Christensen, J. Am.
Chem. Soc., 1966, 88, 2641.
¶ The attack from the opposite side of the 5Ј-OH residue might be
sterically and/or electrostatically preferable, although the detail is not
clear.
The argument presented here is one of the possible mechanisms for
the regioselective scission of cAMP. Information on the life-time of the
pentacoordinated intermediate and on the rate of its pseudo-rotation is
required for further discussion.
Paper 6/04305D
Received 19th June 1996
Accepted 2nd October 1996
78
J. Chem. Soc., Perkin Trans. 2, 1997