Solvent deuterium kinetic isotope effects for the methanolyses of neutral C=O, P=O and P=S esters catalyzed by a triazacyclododecane : Zn 2+-methoxide complex

Article abstract of DOI:10.1039/b512378j

The methanolyses of several organophosphate/phosphonate/phosphorothioate esters (O, O-diethyl O-(4-nitrophenyl) phosphate, paraoxon, 3; O, O-diethyl S-(3,5-dichlorophenyl) phosphorothioate, 4; O-ethyl O-(2-nitro-4-chlorophenyl) methylphosphonate, 5; O, O-dimethyl O-(3-methyl-4-nitrophenyl) phosphorothioate, fenitrothion, 6; O-ethyl S-(3,5-dichlorophenyl) methylphosphonothioate 7) and a carboxylate ester (p-nitrophenyl acetate, 2) catalyzed by methoxide and the Zn²⁺(^-OCH₃) complex of 1,5,9- triazacyclododecane (1 : Zn²⁺(^-OCH₃)) were studied in methanol and d₁-methanol at 25°C. In the case of the methoxide reactions inverse skie's were observed for the series with values ranging from 2 to 1.1, except for 7 where the k_D/k_H = 0.90 ± 0.02. The inverse k_D/k_H values are consistent with a direct nucleophilic methoxide attack involving desolvation of the nucleophile with varying extents of resolvation of the TS. With the 1 : Zn ²⁺(^-OCH₃) complex all the skie values are k_D/k_H = 1.0 ± 0.1 except for 7 where the value is 0.79 ± 0.06. Arguments are presented that the fractionation factors associated with complex 1 : Zn²⁺(^-OCH₃) are indistinguishable from unity. The skie's for all the complex-catalyzed methanolyses are interpreted as being consistent with an intramolecular nucleophilic attack of the Zn²⁺-coordinated methoxide within a pre-equilibrium metal : substrate complex. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b512378j

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A R T I C L E
Solvent deuterium kinetic isotope effects for the methanolyses of
neutral C=O, P=O and P=S esters catalyzed by a
2+
triazacyclododecane : Zn -methoxide complex
Chris Maxwell, Alexei A. Neverov and R. Stan Brown*
Department of Chemistry, Queen’s University, Kingston, Ontario, Canada K7L 3N6.
E-mail: rsbrown@chem.queensu.ca; Tel: +1 613 533 2400
Received 2nd September 2005, Accepted 17th October 2005
First published as an Advance Article on the web 7th November 2005
The methanolyses of several organophosphate/phosphonate/phosphorothioate esters (O,O-diethyl
O-(4-nitrophenyl) phosphate, paraoxon, 3; O,O-diethyl S-(3,5-dichlorophenyl) phosphorothioate, 4; O-ethyl
O-(2-nitro-4-chlorophenyl) methylphosphonate, 5; O,O-dimethyl O-(3-methyl-4-nitrophenyl) phosphorothioate,
fenitrothion, 6; O-ethyl S-(3,5-dichlorophenyl) methylphosphonothioate 7) and a carboxylate ester (p-nitrophenyl
2
+
−
2+
−
acetate, 2) catalyzed by methoxide and the Zn ( OCH
3
) complex of 1,5,9-triazacyclododecane (1 : Zn ( OCH ))
3
◦
were studied in methanol and d
1
-methanol at 25 C. In the case of the methoxide reactions inverse skie’s were
observed for the series with values ranging from 2 to 1.1, except for 7 where the k
/k values are consistent with a direct nucleophilic methoxide attack involving desolvation of the nucleophile with
varying extents of resolvation of the TS. With the 1 : Zn ( OCH
except for 7 where the value is 0.79 ± 0.06. Arguments are presented that the fractionation factors associated with
complex 1 : Zn ( OCH ) are indistinguishable from unity. The skie’s for all the complex-catalyzed methanolyses are
D
/k
H
= 0.90 ± 0.02. The inverse
k
D
H
2
+
−
3
) complex all the skie values are k /k
D
H
= 1.0 ± 0.1
2
+
−
3
2
+
interpreted as being consistent with an intramolecular nucleophilic attack of the Zn -coordinated methoxide within
a pre-equilibrium metal : substrate complex.
Introduction
to the fact that there are likely two or more catalytic functional
groups that act in a base/acid role to promote the phosphate
Metal ion catalyses of the hydrolyses of carboxylate esters,
2+
−
9b
2+
cleavage. Roles for the Mg – OH as a general base, or Mg
acting as a Lewis acid to assist the departure of the oxyanion
1
2
amides and phosphate mono-, di- and triesters have been
extensively studied to ascertain the practical applications and as
an aid to understanding the mechanism of action of hydrolytic
9a,c
leaving group
have been suggested. Interpretation of skie
experiments dealing with enzymatic systems is fraught with
3
metalloenzymes. Many reports have appeared concerning the
metal catalyzed hydrolyses of neutral phosphate triesters and
a lesser number on neutral phosphonate diesters
to their importance as acetylcholinesterase inhibitors. In the
bulk of these studies the most active catalytic species were
10
difficulties, as Kresge has pointed out, since there are numerous
4
exchangeable-proton and solvation sites on the enzyme which
could contribute to the observed effect but are not directly
associated with the catalytic machinery.
4
q,v,w,x,y
due
Recently we reported examples of the methanolyses of car-
x+
−
identified as the M – OH forms generated at high pH through
ionization of a metal-bound water. The general consensus for
11
12
boxylate esters, phosphate and phosphorothioate triesters
13
3+
2+
and some phosphonates promoted by La , 1 : Cu and
x+
the hydrolytic mechanism of all these esters is that the M –
2+
1
: Zn , in methanol solution under buffered conditions
−
4b
OH acts as a nucleophile, either directly on the C=O or
s 14,15
to control pH.
The 1,5,9-triazacyclododecane complexes
s
P=O unit without coordination, or more probably through a
2+
2+
of Zn and Cu , as their mono-methoxy forms (1), are
monomeric throughout the pH regions of interest for catalysis.
4
5
pre-equilibrium metal–ester binding or a hybrid mechanism.
Alternative mechanisms have been proposed where an external
s
s
s
s
2+
The pK
9
a
for ionization of the 1 : Zn –HOCH complex is
12e
3
−
x+
6
OH nucleophilically attacks a M -coordinated substrate or
12d
2+
.1 while that for the 1 : Cu HOCH complex is 8.75.
3
−
where a metal-coordinated OH or external hydroxide acts as a
2+
−
The stoichiometric simplicity of the 1 : M ( OCH ) system
as well as being able to use it to set the pH or pD of
the solution at values corresponding to the pK
3
7
general base.
s
s
s
s
In ideal cases experimental evidence for the nucleophilic
or general base mechanisms should be provided through the
use of solvent deuterium kinetic isotope effects (skie) but to
s
s
a
when the [1
2+
−
2+
:
M ( OCH
3
)]/[1 : M (LOCH
3
)] ratio is unity (L = H, D)
16,17
makes it a good candidate for skie studies
As recognized
7
our knowledge there is a paucity of these reported for the
18
19
earlier by Gold and Schowen, the choice of methanolysis
also removes the problem of an internal fractionation factor for
metal catalyzed hydrolysis of neutral carboxylate and phosphate,
phosphorothioate, phosphonate or phosphonothioate esters.
There are a few skie studies reported for metal catalyzed hydrol-
yses of phosphate diesters and ribozyme-catalyzed cleavage of
phosphate diesters where the binding of the anionic phosphate
−
the HO that is associated with hydroxide-promoted hydrolyses
and introduces additional complications when assessing skie
8
−
processes in water. In what follows we report the skie for OCH
3
9
substrates to the metal centres is far stronger than is the case
with neutral substrates. For simpler cases where metal ions were
8
involved in the cleavage of phosphate diesters skie values of
1
.0 ± 0.1 were interpreted as indicating a nucleophilic rather
than a general base mechanism because there was no strong
primary effect as is expected for a ‘proton in flight’ or one
being transferred between a base and nucleophilic water during
the reaction. The situation with the Mg -dependent ribozyme-
catalyzed phosphoryl transfer reactions is more complicated due
2
+
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 2 9 – 4 3 3 6
4 3 2 9

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ing to the destruction of starting material (paraoxon; k =
2
68 nm) or the formation of products (O,O-diethyl S-(3,5-
dichlorophenyl)phosphorothioate; k = 281 nm, fenitrothion; k
=
335 nm, 4-nitrophenyl acetate; k = 339 nm) with a Cary
◦
1
00 Bio UV-Vis spectrophotometer thermostated at 25 C. The
absorbance vs. time data were fit to a standard first order
exponential equation to obtain the pseudo-first order rate
constants, kobs. The rates of reaction were measured in duplicate
−
3
at different catalyst concentrations from 0.2–3 mmol dm for 1
2
+
−3
:
Zn and from 3–30 mmol dm for the methoxide reactions.
The second order rate constants for catalysis of methanolysis
of 2–7 were determined as the gradients of the kobs vs. [active
s
s
catalyst]. After each kinetic run in non-deuterated solvent, pH
was measured with an Accumet Ag/AgCl electrode.
For consistency, kinetic runs in d -methanol utilized the same
1
stock solutions that were used in protiated methanol. This
introduces some protium into the solution but it is never more
than 9.6% and has at most a 5% effect on the skie for the most
inverse case (methoxide + 2) and very little effect on the results
2
+
−
and 1 : Zn ( OCH
3
)-catalyzed methanolysis of some neutral
2+
−
with 1 : Zn ( OCH
3
) since all the examples have k
D
H
/k values
carboxylate and phosphorus esters 2–7.
near unity.
Experimental
Results
i) Materials
Given in Table 1 are the second order rate constants determined
for the methoxide and 1 : Zn ( OCH
of 2–7 determined in methanol and d
were determined from the gradients of plots of the pseudo-first
order rate constant (kobs) for methanolysis of each substrate as
2
+
−
Anhydrous methanol (99.8%), methanol-d
NaOMe (0.5 M), NBu
1
(99 atom%),
3
) promoted methanolyses
-methanol. The constants
4
OH (1.0 M) were from Aldrich. Zn(OTf)
2
1
(
98%) was from Acros Organics. Paraoxon (98.4%) was from
Chem Service Ltd. p-Nitrophenyl acetate (2, Aldrich) was
recrystallized from ethyl acetate and acetic anhydride. Feni-
trothion (6, 96.7%) was from Sumitomo Chemicals and used as
received. O,O-Diethyl S-(3,5-dichlorophenyl) phosphorothioate
−
2+
−
a function of [ OCH
concentrations of reactant in duplicate. The skie is given as
/k which is generally inverse for all the methoxide reactions
except with 7 and indistinguishable from unity for all the metal
3
] or [1 : Zn ( OCH )] using at least three
3
k
D
H
12b
(
4) was supplied by Mr Tony Liu from an earlier study. O-
Ethyl O-(2-nitro-4-chlorophenyl) methylphosphonate (5) was
prepared by and its kinetics of methanolysis determined by
Ms Roxanne Lewis and 1,5,9-triazacyclododecane was sup-
plied by Mr Graham Gibson. O-Ethyl S-(3,5-dichlorophenyl)
methylphosphonothioate (7) was synthesized and its kinetics of
ion catalyzed reactions except with 7 where the value is k
= 0.79 ± 0.05.
D
/k
H
13
Discussion
20
methanolysis determined by Ms Stephanie Melnychuk.
i. General considerations for fractionation factor analysis.
21
The solvent kie can be predicted as:
ii) Methods
TS
GS
k
D
/k
H
= P
i
(1 − x + xφ
i
)/P
j
(1 − x + xφ
j
)
(1)
s
s
UV/vis kinetic determinations and pH measurements were
done using instruments and methods described earlier.
Stock solutions of the substrates (5 mmol dm ), NaOMe
1
1–13
φTS and P
GS
where P
i
j
φ
are the products of the fractionation
−
3
factors (φ) for all exchangeable i and j protons (L = H, D) in
the transition (TS) and ground states, and x is the mole fraction
of deuterium in the solvent mixture. The fractionation factors
for hydrogens refer to the tendency of H or D to accumulate
at a given site relative to bulk solvent. In less precise terms
they refer to the ‘tightness of bonding’ and the general rule
is that the heavier isotope accumulates in the stronger bond.
Fractionation factors are significantly less than unity for L’s
being transferred or “in flight” between O and N, or O and O
as part of the rate-limiting step. In these cases normal primary
−
3
−3
(
(
25 mmol dm ), NBu
50 mmol dm ) and 1,5,9-triazacyclododecane (50 mmol dm )
4
OH (25 mmol dm ), Zn(OTf)
2
−
3
−3
were made in anhydrous methanol. The catalyst for kinetic
runs was formed in situ by addition of known aliquots of
Zn(OTf)
2
, 1,5,9-triazacyclododecane and NaOMe or NBu OH
4
to anhydrous methanol or methanol-d such that the final volume
in each UV cell was 2.5 ml. pH was controlled in methanol
at 9.14 by maintaining a constant ratio of Zn(OTf) : 1,5,9-
s
s
2
triazacyclododecane : base = 1 : 1 : 0.5. The kinetics were
measured by monitoring the change in absorbance correspond-
dkie’s of k
H
/k
D
> 1 (generally from 2–4) are expected unless other
2+
−
Table 1 Solvent deuterium kinetic isotope effects for the reactions of methoxide and 1 : Zn ( OCH
3
) with esters 2–6
OMe
−1
3
−1
1 : Zn(OMe)
−1
3
−1a
k
2
/mol dm s
k
2
/mol dm s
b
b
Subst.
CH
3
OH
CH
3
OD
k
D
/k
H
CH
3
OH
CH
3
OD
k
D
/k
H
2
3
4
216 ± 6
430 ± 9
2.0 ± 0.1
1.10 ± 0.02
1.5 ± 0.04
1.47 ± 0.08
1.3 ± 0.03
0.90 ± 0.02
8.4 ± 0.3
0.48 ± 0.007
0.83 ± 0.07
517 ± 3
9.4 ± 0.3
0.47 ± 0.007
0.83 ± 0.04
510 ± 20
1.1 ± 0.1
0.98 ± 0.02
1.0 ± 0.1
0.016 ± 0.0002
0.155 ± 0.003
14.3 ± 0.1
0.018 ± 0.0002
0.244 ± 0.003
21 ± 1
c
5
0.98 ± 0.04
1.1 ± 0.1
−
4
−4
6
7
(5.9 ± 0.02) × 10
(7.5 ± 0.2) × 10
6.3 ± 0.2
6.9 ± 0.3
d
2.17 ± 0.03
1.96 ± 0.02
95.2 ± 1.4
75.7 ± 4.6
0.79 ± 0.06
a
2+
−
c
b
Determined at 1 : Zn : ( OCH
3
) = 1 : 1 : 0.5. Computed as gradient of kobs vs. [catalyst] without correction for amount of protium which can be
d
as high as 9.6%; see ref. 42. From ref. 13. From ref. 20.
4
3 3 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 2 9 – 4 3 3 6

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compensating factors, such as changes in solvation, are at play. In
hydrogen bonding situations where the overall bonding is loose,
the φ values are also less than unity and these can contribute
secondary effects of solvation which may significantly alter the
22
overall dkie.
1
8a
23
Gold and Grist and More O’Ferrall determined that the
−
methanolic methoxide ion exists as MeO (LOMe)
3
where each
of the three solvating hydrogen bonding L has a fractionation
factor value of φ = 0.74; this value will be used for the
ground state for discussing the methoxide dependent reactions
below. There are a few fractionation factors available for water
3
+
2+
3+ 24
ii. General mechanistic possibilities for lyoxide reactions with
carboxylate and phosphate esters
solvated metal ions such as Fe , Mn and Cr
as well
2
+
2+ 25
as the alkali metal cations, Ag and Cd
and these are
close to unity indicating that the associated solvent does not
behave very differently from bulk water. As far as we are aware
To interpret the skie one needs first to ascertain the rate-
limiting step for the reactions in question. Schemes 1 and 2
illustrate the two general nucleophilic (Nuc) and general base
x+
−
no fractionation factors have been published for M ( OR)
systems, although a value of 0.72 was interpreted from NMR
(
GB) mechanisms where the bold L represents the exchangeable
26
II
T
2
measurements for the high pH forms of Co carbonic
H or D in the ground and transition states. Although most of
anhydrase isozymes I and II in water where the active site
−
HO - promoted hydrolyses of carboxylate esters are interpreted
II
−
2+
−
comprises a His
3
-bound Co -( OL). In 1 : Zn ( OCH
3
) the
28
as nucleophilic, Marlier has proposed a GB mechanism for
2
+
Zn electrostatically stabilizes the coordinated methoxide which
the alkaline hydrolysis of methyl formate based on heavy atom
s
s
accounts for the fact that the pK
a
of methanol is reduced from
29
kinetic isotope effects A more recent analysis of a proton
12b
2+
1
8.13 to 9.14 when coordinated to the Zn . Due to the reduced
inventory study of the alkaline hydrolysis of ethyl acetate also
need for H-bonding stabilization of the complex we suggest the
working model 8, where the fractionation factors associated with
the N–L groups are unity and that for the two possible solvating
LOMe groups is 1.0 or slightly less, but nowhere as low as for
free methoxide. In support of the near unit fractionation factor
we have been able to confirm the φ of 0.74 for the solvating
30
was interpreted in support of the GB mechanism, although
31
not uniquely so in our opinion. As far as we know, the main
role for lyoxide reaction with phosphate triesters is deemed to
32
be Nuc although weakly nucleophilic additives can function
in GB roles as was demonstrated by a key study of the acetate
33
promoted methanolysis of some phosphate triesters
1
methanols of methoxide using the H NMR methodology of
Possible variants of the Nuc and GB mechanisms for car-
boxylate and phosphate esters involve concerted or stepwise
reactions. Transfer of an acetyl group from p-nitrophenyl acetate
to phenolate and oxyanion acceptors is probably a concerted one
18a
Gold but have not been able to detect any effect of added 1 :
2
+
−
−3
Zn ( OCH
3
) up to 10 mmol dm on the exchangeable proton
13
peak position relative to the C satellite of CH
3
OL. The inability
to observe a detectable effect with 1 : Zn ( OCH ) suggests that
) in 8 is sufficiently weak that
the hydrogen bonds to the coordinated methoxide cannot be
2
+
−
3
34a
step reaction with little imbalance between bond formation
2
+
−
the solvation of the Zn ( OCH
3
34b
and cleavage. Shames and Byers suggest that oxyanions which
are more basic than the leaving group react with p-nitrophenyl
acetate through a transition state which is nearly tetrahedral and
with very little barrier to breakdown which is not necessarily at
variance with a concerted process. Finally, Hengge and Hess
conclude from heavy atom kinetic isotope effects that hydroxide
27
distinguished from those in bulk water. This lack of solvation
might be one of the reasons that 1 : Zn ( OCH ) is such an
2
+
−
3
effective catalyst since it does not take much energy to remove a
H-bond to liberate a free electron pair for the catalytic step.
ꢀ
ꢀ
Scheme 1 Nucleophilic mechanisms for attack of methoxide. (Carboxylate esters, X = C, R = CH
3
. Phosphorus esters, R = ethoxy, X = P(alkyl),
P(ethoxy)).
ꢀ
ꢀ
Scheme 2 General base mechanisms for methoxide reaction. (Carboxylate esters, R = CH
3
; X=C. Phosphorus esters, R = ethoxy, X= P(alkyl),
P(ethoxy)).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 2 9 – 4 3 3 6
4 3 3 1

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and hexafluoroisopropanolate react with 2 via a concerted
(O-ethyl S-(3,5-dichlorophenyl) methylphosphonothioate). The
value we obtained for paraoxon is experimentally identical to
34c
mechanism.
By contrast, the lyoxide reactions of 2-aryloxy-2-oxo-1,3-
3
3
the k
D
/k
H
= 1.2 provided by Schowen for the methanolysis of
35,36
dioxaphosphorinanes
have been discussed in terms of two
O,O-dimethyl-O-(p-nitrophenyl) phosphate (methyl paraoxon)
implying a negligible steric effect on the inverse nature of the
skie. That none of the skie values for the phosphorus esters is
as inverse as found for the carboxylate ester 2 suggests there is
some additional solvation of the transition states for phosphate
methanolysis which is not present in the solvolysis of 2.
Resolvation of the TS offsets the desolvation of the nucleophile
bringing the observed skie closer to unity as observed, but
the skie experiments do not indicate where such resolvation
step processes that proceed via rate limiting formation of a 5-
coordinate intermediate. The relatively low Brønsted blg values
−
−
of −0.4 obtained for the HO or CH
3
O nucleophiles with
these substrates are consistent with little cleavage of the P–
OAr bond in the TS. Hydroxide promoted hydrolyses of O,O-
3
7,38
diethyl O-aryl phosphate triesters
and O,O-diethyl S-aryl
37
phosphorothiolates give relatively low blg values of −0.4 and
was discussed in terms of a common mechanism involving
−
33
nucleophilic attack of HO , although it was not specified in
occurs. Schowen suggests, on the basis of proton inventory
the latter study whether the reaction of these substrates is a
two step one or concerted. Williams and co-workers provided
evidence for a concerted transfer of the diphenylphosphoryl
data and a comparison with an observed acetate promoted
43,44
general base methanolysis reaction
of methyl paraoxon, that
methoxide promoted methanolysis probably occurs through a
transition state characterized by a “one proton bridge plus
solvation model”. Although the position of the proton bridge
is not known, if it occurs between the methoxide and a second
attacking methanol this would be almost equivalent to a general
base mechanism, but one with little removal of the bridging
proton in the TS since its fractionation factor is never less than
0.67.
39
group between phenoxide anions in water and considered that
−
HO reacting with diethyl aryloxy phosphates was probably
concerted but with little cleavage of the ArO–P bond. This is
1
8
consistent with the O-phenoxy kinetic isotope effect of 1.006
−
40
for HO -promoted cleavage of paraoxon 3 that was interpreted
as having a P–OAr bond order of 0.75 within an “S 2-like
N
transition state of an associative mechanism with concerted,
asynchronous departure of the leaving group.”
1
2b,13
Recent studies
found Brønsted blg dependencies of −0.70,
−
0.76 and −0.76 respectively for the methoxide promoted
iii. Skie for the methoxide reactions of carboxylate and neutral
phosphate esters
methanolysis of three series of O,O-diethyl O-aryl phos-
phates, O,O-diethyl S-aryl phosphorothioates and O-ethyl O-
◦
aryl methylphosphonates at 25 C. These are consistent with
a. Carboxylate esters. Inverse k
D
/k
H
values of 1.9 for
two step or concerted reactions where the charge on the aryloxy
or arylthio groups in the TS of the three series is +0.17,
methanolysis of phenyl benzoate at 25 C and 2.6 for the
41
methanolysis of p-nitrophenyl acetate at −78 C are con-
sistent with a Nuc but not GB mechanism. The k /k
.84 for methoxide reacting with phenyl acetate at 25 C was
−
0.2, and −0.26 respectively. The skie’s for these phosphorus
D
H
=
esters do not provide additional information to distinguish
stepwise from concerted mechanisms, but combining the skie,
1
19b
rationalized in terms of the Nuc mechanism of Scheme 1. One
of the three solvating LOMe groups on methoxide is removed to
liberate a nucleophilic lone pair with the two remaining solvating
LOMe molecules loosening their association in the transition
state to have φ = 0.88; the computed skie for this process is
33
proton inventory and the Brønsted blg data suggest possible
TS structures 9 or 10 with the P–XAr bond being intact or
partially cleaved and with one specific stronger H-bonding
(
proton bridging) interaction along with additional numbers of
non-specific hydrogen bonds. The transition state contribution
of these (TSC) in either 9 or 10 can be computed from eqn (2)
for 3–7 as 0.45, 0.61, 0.60, 0.53 and 0.36 respectively when φgs
2
3
k
D
/k
H
= (0.88) /(0.74) = 1.91.
The skie for methanolysis of p-nitrophenyl acetate (2) found
◦
here is k
D
/k
H
= 2.0 ± 0.1 at 25 C which, when interpreted
=
0.74.
as above, gives a fractionation factor for the two TS solvating
2
3
42
protons of 0.9 : k
D
/k
H
= (0.9) /(0.74) = 2.0. That all skie
3
k
D
/k
H
= TSC/(1 − n + nφgs
)
(2)
values for methanolysis of aryl esters are substantially inverse
effectively rules out the GB mechanism shown in Scheme 2.
That mechanism, with the proton in flight having a predicted
φ value between 0.4–0.25 (for a primary k
.5–4) and with φ values of 0.9 for the two residual solvating
LOMe molecules, would have a computed normal skie of k /k
1.25–2.0.
The methoxide reaction of a series of aryloxy acetates
H
/k
D
contribution of
2
H
D
=
11b
generates a Brønsted blg value of −0.66 which is consistent
34
with either a concerted reaction or a two step process with rate-
limiting methoxide addition to create and unstable tetrahedral
intermediate with essentially no charge on the departing group.
The skie data do not add to the two step/concerted case
other than to imply that resolvation of either TS must lag far
behind desolvation of the nucleophile, a conclusion similar to
one we reached for the alkaline hydrolysis of formamide and
31
ethyl acetate on the basis of proton inventory data. Such
resolvation of the TS, if significant, would introduce additional
φ contributions of <1 into the numerator of eqn (1) leading to
2
+ −
iv. 1 : Zn ( OCH ) promoted methanolysis of 2–7
3
Numerous authors have considered that invoking a dual role
for the metal ion (as a Lewis acid and deliverer of metal-bound
lyoxide) requires that the metal promoted: lyoxide reaction is
faster than lyoxide alone.
catalyzed reactions of all the phosphorus esters
k
D
H
/k values which are closer to unity than observed.
b. Phosphorus esters
4b,h,m,p,5,11,12,13
2+
−
Since the 1 : Zn ( OCH
3
)-
11,12,13,20
Given in Table 1 are respective values of k
D
/k
H
= 1.1, 1.5,
presented
1
.47, 1.3 and 0.90 for the methoxide promoted methanol-
ysis of phosphorus esters 3 (paraoxon), 4 (O,O-diethyl-S-
3,5-dichlorophenyl) phosphorothioate), 5 (O-ethyl-O-(2-nitro-
in Table 1 are faster than the methoxide reactions, we envision
a common mechanism with a rapid pre-equilibrium binding of
the metal complex to the P=O or P=S unit with subsequent
(
4
-chlorophenyl) methylphosphonate), 6 (fenitrothion) and 7
intracomplex metal-bound methoxide attack although there are
4
3 3 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 2 9 – 4 3 3 6

View Article Online
some kinetically equivalent alternatives that can be ruled out
later.
mechanisms for the metal-catalyzed reactions of the ensuing
complexes which are divided into two kinetically equivalent
main classes: 1) an intramolecular process where a metal-
The situation with carboxylate esters is more difficult to
analyze and the interpretation depends on whether the leaving
2
+
bound methoxide acts on a transiently M -bound substrate
(the IM process); or 2) an external methoxide reacting with a
45
group is good or bad. Since the reported reaction of hydroxide
with the carboxylate ester 2 was 230 times faster than that of
2
+
transient M -bound substrate (the EM process). Each of these
could involve Nuc or GB processes and each could be concerted
or two steps. Schemes 3 and 4 show the possibilities where the
slow step of the reactions involves the IM and EM attack on the
complex either directly or as a GB via the concerted or stepwise
processes.
2
+
−
4b
1
: Zn ( OH), Kimura and Koike concluded that a simple
bimolecular mechanism was predominant for the latter where
2
+
−
the “Zn - bound hydroxide (less basic than free OH ion) acts
−
merely as a nucleophile (or general base to generate OH) to
the carbonyl group”. Suh, Son and Suh subsequently suggested
6
that this mechanism is incorrect and that a kinetically equivalent
process occurs where a metal–ester complex suffers rate limiting
Some of the possibilities can be ruled out. As described
above, the reactions of a series of acetate esters are two step
ones with 2 falling in a domain where the RDS is attack on
−
2+
11b
attack of external OH to form a M -bound tetrahedral
2
+
−
intermediate. Our own study of the 1 : Zn ( OCH
3
) promoted
a transiently coordinated substrate. All the phosphate esters,
20
methanolysis of an extensive series of carboxylate esters with
including 7 have large negative Brønsted blg values signifying
11b
good and poor leaving groups revealed a downward break
in the Brønsted plot, consistent with a two step mechanism
with a change in rate-limiting step (RDS) due to partitioning
of a metal-coordinated tetrahedral intermediate, the formation
and breakdown of which is rate limiting for good and poor
leaving groups respectively. Importantly, for all the cases with
poorer aryloxy leaving groups than 4-nitrophenoxy such as 4-
extensive cleavage of the P–OAr or P–SAr bonds in the transition
12b,13,20
state which is consistent with a concerted reaction.
The
near unity skie values for all the species allow us to rule out the
IM mechanism where there is a GB role for the methoxide. Large
normal kie’s of k
H
/k
D
> 2 are commonly found for general base
catalyzed processes whereas direct nucleophilic addition usually
47
involves little or no isotopic distinction unless large secondary
effects associated with solvation changes are at play which is not
the case here. Since the fractionation factors associated with the
initial complex 8 are unity (vide supra), the TSC in eqn (2) for the
metal catalyzed reactions of 2–6 must be essentially unity as well,
so there cannot be any proton in flight or extensive H-bonding
resolvation of the TS having a φ < 1.0, otherwise the skie would
be normal and substantially >1. With 7 the skie is normal but
Cl-, 4-OCH
3
-, 4-H-, 2,4-dimethyl- and 2,3,5-trimethylphenoxy,
2+
−
methoxide is significantly less reactive than is 1 : Zn ( OCH
3
).
However with 4-nitrophenoxy and all leaving groups better
than that, methoxide is the better nucleophile. This reinforces
the caveat that proposing a catalytic mechanism based on
the results with a limited number of substrates, particularly
those containing examples limited to the good leaving group
46
p-nitrophenoxy, is often incorrect.
slightly so at k
D
/k
H
= 0.79 which is not large enough to strongly
If we accept the reasonable premise that there is a common
support a GB process but may indicate some extra transition
state solvation relative to the starting materials. The preferred
IM process consistent with all the results is shown in Scheme 3
2
+
pre-equilibrium binding of the Zn -complex to both the
phosphorus and carboxylate esters, there are at least eight
2+
−
ꢀ
Scheme 3 Intramolecular nucleophilic and general base mechanisms for catalysis by 1 : Zn ( OCH
C. Phosphorus esters, R = ethoxy, X = P(alkyl), P(ethoxy)).
3
). (Carboxylate esters, R = CH
3
; X =
ꢀ
2+
ꢀ
Scheme 4 External methoxide nucleophilic and general base catalyzed methanolysis of 1 : Zn + substrate complex. (Carboxylate esters, R = CH
3
;
ꢀ
X = C. Phosphorus esters, R = ethoxy, X = P(alkyl), P(ethoxy)).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 2 9 – 4 3 3 6
4 3 3 3

View Article Online
2
+
and proceeds by the equilibrium formation of a metal–substrate
complex 11 followed by the rate limiting nucleophilic TS 12 in
which the C–XAr bond is intact for carboxylate esters and the
P–XAr bond is partially cleaved for phosphate esters.
requires that the loss of the leaving group also involves Zn
coordination but this is not required for good leaving groups.
The preferred intramolecular mechanism involving cis bind-
ing of a substrate and internal nucleophilic attack through a
four-membered TS has been suggested many times before, but
usually without detailed skie, Brønsted or other studies with
an extensive series of substrates. Its attractiveness is simplicity,
and its acceptance probably inspired by the earlier mechanisms
elucidated for the hydrolysis of several exchange inert cis-
Co ( OH) : (amide), : (ester) and : (phosphate) complexes
which are convincingly shown by O-isotope labeling and
other techniques to involve intramolecular O-transfer to the
In Scheme 4 is the kinetically equivalent EM process for
the nucleophilic and general base possibilities. The ground
state contributions to the fractionation factors are ∼1.0 for
2
+
24,25
the 1 : Zn (HOCH
3
) complex
and 0.74 for each of the
solvating methanols on the methoxide. The predicted k
TSC/(1.0)(0.74) , so the TSC would have to be 0.36–0.44 in
D
/k
H
=
3
III −18
1
8
order to accommodate the essentially unity skie observed for
−
18
all species. Given the above skie results for OCH
3
promoted
33
50
methanolysis of 2–7 and methylparaoxon, a direct nucleophilic
role for external methoxide does not seem possible unless
there is considerable resolvation of TS 15. The GB process
proceeding through TS 16 with a proton in flight is possible
mathematically although we can rule this out, at least for the
phosphorus esters, with other evidence. Simple consideration of
the observed second order rate constants for the metal catalyzed
reaction of 5 and reasonable values for the equilibrium binding
constants allows us to rule out the external methoxide Nuc or
GB processes since the computed rate constants for external
substrate.
Acknowledgements
The authors gratefully acknowledge the financial assistance
of the Natural Sciences and Engineering Research Council of
Canada, the Canada Foundation for Innovation, Queen’s Uni-
versity and the United States Department of the Army, Army
Research Office, Grant No. W911NF-04-1-0057andtheDefence
Threat Reduction Agency, Joint Science and Technology Office
2
+
51
attack on a 1 : Zn -bound substrate exceeds the diffusion limit
(06012384BP). Chris Maxwell thanks Queen’s University for a
9
−1
3
−1 48
6
of 5 × 10 mol dm s . It is customarily assumed that the
Summer Work Experience Program grant and Natural Sciences
and Engineering Council of Canada for additional financial
support. We are also indebted to Ms Stephanie Melnychuk, Ms
Roxanne Lewis and Ms Josephine Tsang for technical assistance
in performing some of the experiments. Finally they are grateful
to Professor David Evans (Harvard University) and Professor
Jerry Kresge (University of Toronto) for helpful discussions.
equilibrium binding constant for various metal ion complexes
−
1
3
with neutral C=O or P=O substrates is ∼1 mol dm . We also
assume this number to be appropriate for methanol noting
that there is no saturation behaviour of the reaction kinetics
−
3
at concentrations of catalyst up to 10 mmol dm . In the case
of 1 mmol dm of [1 : Zn ] at pH 9.14, the [ OCH
−
3
2+
s
s
−
3
] =
−
7.65
−3
10
mol dm and the computed second order rate constant
1
0
−1
3
−1
for methoxide attack on 5 would be 2.1 × 10 mol dm s , a
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1
1
005, 3, 4082.
3
base and metal ions which were formulated from HOCH , and in the
15
most extreme cases the deuterated medium contained less than 9.6%
of protium. One can determine that from eqn (1) that the methoxide
reaction with p-nitrophenyl acetate in a medium containing 0.9 mole
of the IUPAC, Compendium of Analytical Nomenclature. Definitive
rd
Rules 1997 3 edn, Blackwell, Oxford, UK, 1998. If one calibrates the
measuring electrode with aqueous buffers and then measures the pH
fraction of D rather than 1.0 influences the k
D
H
/k by only 5% (from
w
w
of an aqueous buffer solution, the term pH is used; if the electrode
2.0 to 1.84) which is well within the experimental uncertainty of the
kinetic measurements. For cases where the dkie is closer to unity, the
corrections are even smaller. For this reason we have simply reported
the deuterium rate constants in Table 1 as the gradients of the plots
of kobs vs. [catalyst] without any correction for the amount of protium
in solution.
is calibrated in water and the ‘pH’ of the neat buffered methanol
w
solution then measured, the term s pH is used; and if a correction
factor of −2.24 (in the case of methanol) is subtracted from the latter
s
reading, then the term pH is used.
s
−
16.77
1
1
5 Given that the autoprotolysis constant of methanol is 10
−
3 2 s
(
mol dm ) , neutral pH in methanol is 8.4. E. Bosch, F. Rived,
43 In the study reported in ref. 33, Bryan, Schowen and Schowen
observed that acetate promoted methanolysis of methyl paraoxon
s
M. Ros e´ s and J. Sales, J. Chem. Soc., Perkin Trans. 2, 1999, 1953.
6 Note that for this study it is not necessary to know the exact value
gave a normal skie of k
H
/k
D
= 1.7-1.8, attributable to a ‘one proton
s
s
2+
for the pK
a
of 1 : M (LOCH
3
3
) in DOCH
)] ratio is unity by definition makes
a
. On the other hand, it is reported that in
3
since the setting of the [1
bridge’ with a relatively low fractionation factor of ∼0.57.
44 V. E. Bel’skii, L. A. Kudryavsteva, K. A. Derstuganova, S. B.
Federov and B. E. Ivanov, Zh. Obshch. Khim., 1980, 50, 1997 report
2+
−
2+
:
M ( OCH
the pD equal to the pK
)]/[1 : M (LOCH
3
s
s
s
s
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 2 9 – 4 3 3 6
4 3 3 5

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that triethanolamine catalysis of the ethanolysis of diphenyl-p-
indicates the reaction would have to exceed the diffusion limit by
50-fold.
nitrophenyl phosphate has a skie of k
H
/k
D
= 2 consistent with a
general base mechanism.
50 (a) D. A. Buckingham, J. MacB. Harrofield and A. M. Sargeson,
J. Am. Chem. Soc., 1973, 96, 1726; (b) E. Baraniak, D. A. Bucking-
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1719.
4
4
5 W. P. Jencks, J. Am. Chem. Soc., 1068, 09, 2622.
6 (a) F. M. Menger and M. Ladika, J. Am. Chem. Soc., 1987, 109, 3145;
(
b) J. Chin, Acc. Chem. Res., 1991, 24, 145.
4
4
7 S. L. Johnson, Adv. Phys. Org. Chem., 1969, 91, 2799.
8 (a) K. N. Dalby and W. P. Jencks, J. Am. Chem. Soc., 1997,
1
19, 7271 and references therein; (b) R. A. McClelland, V. M.
Kanagasabapathy, N. S. Banait and S. Steenken, J. Am. Chem. Soc.,
991, 113, 1009; (c) R. S. McClelland, F. L. Cozens, S. Steenken, T. L.
1
Amyes and J. P. Richard, J. Chem. Soc., Perkin Trans. 2, 1993, 1717.
9 A similar computation using the second order rate constant for the 1 :
51 The content of the information does not necessarily reflect the
position or the policy of the federal government, and no official
endorsement should be inferred.
4
2+
obs
−3 −1
s
13
Cu catalyzed reaction of 5 (k
2
= 2100 mol dm
s
at pH 8.75)
s
4
3 3 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 2 9 – 4 3 3 6