Comparison of Cu(II)-promoted leaving group stabilization of the cleavage of a homologous set of phosphate mono-, di-, and triesters in water, methanol, and ethanol

Article abstract of DOI:10.1021/ic300059e

The cleavage of a set of phosphate mono-, di-, and triesters having a Cu(II)-complexed 2-phenanthrolyl group at the ortho-position of a departing phenoxide was studied in water and ethanol. Experimentally observed pH/rate profiles, solvent deuterium kinetic isotope effects, and activation parameters are compared with those obtained in methanol. The pH/rate profile in each solvent exhibits an extended plateau due to solvent attack on forms designated as [Cu(II):1b/c]⁰ for the monoester, [Cu(II):2b]⁺, for the diester, and [Cu(II):3a]²⁺ for the triester. The solvent dkie values (k_H/k_D) for the three complexes are 0.91, 0.95, and 0.83 for decomposition of [Cu(II):1b/c]⁰ in water (W), methanol (M), and ethanol (E), 1.22, 1.09, and 1.29 for [Cu(II):2b]⁺ in W, M, and E, and 1.94, 2.2, and 1.96 for [Cu(II):3a]²⁺ in W, M, and E. Near unit, or slightly inverse values for the monoester are taken as evidence for little involvement of solvent in a highly dissociative TS for P-OAr cleavage, with slightly higher solvent dkie values for the diester signifying the onset of some solvent participation in assisting the nucleophilic displacement. The larger primary dkie for the triester gives evidence for a solvent-assisted delivery of ROH in the cleavage through a more associative mechanism. Activation parameters for each substrate in the solvents are compared, indicating that the transition from methanol to ethanol for each substrate involves a near cancellation of the ΔΔH^? and -TΔΔS^? values (25 °C) so that the respective rates in both solvents are very similar. The transition from alcohol to water produces variable effects, with ΔΔH^? and -TΔΔS^? values canceling for cleavage of the triester and being additive for the mono and diester, explaining their 100-500 rate reduction in passing from methanol to water. The rate enhancing effects of the Cu(II)-promoted leaving group assistance in all three solvents are substantial and estimated at 10 ¹²-10¹⁵ for the monoester, 10¹²-10¹⁴ for the diester, and 10⁵ for the triester relative to their background reactions.

Full text of DOI:10.1021/ic300059e

Article
pubs.acs.org/IC
Comparison of Cu(II)-Promoted Leaving Group Stabilization of the
Cleavage of a Homologous Set of Phosphate Mono-, Di-, and
Triesters in Water, Methanol, and Ethanol
Mark A. R. Raycroft, C. Tony Liu, and R. Stan Brown*
Department of Chemistry, Queen’s University, Kingston, Ontario, Canada K7L 3N6
ABSTRACT: The cleavage of a set of phosphate mono-, di-,
and triesters having a Cu(II)-complexed 2-phenanthrolyl
group at the ortho-position of a departing phenoxide was
studied in water and ethanol. Experimentally observed pH/rate
profiles, solvent deuterium kinetic isotope effects, and
activation parameters are compared with those obtained in
methanol. The pH/rate profile in each solvent exhibits an
extended plateau due to solvent attack on forms designated as
[Cu(II):1b/c]0 for the monoester, [Cu(II):2b]+, for the
diester, and [Cu(II):3a]2+ for the triester. The solvent dkie values (kH/kD) for the three complexes are 0.91, 0.95, and 0.83
for decomposition of [Cu(II):1b/c]0 in water (W), methanol (M), and ethanol (E), 1.22, 1.09, and 1.29 for [Cu(II):2b]+ in W,
M, and E, and 1.94, 2.2, and 1.96 for [Cu(II):3a]2+ in W, M, and E. Near unit, or slightly inverse values for the monoester are
taken as evidence for little involvement of solvent in a highly dissociative TS for P−OAr cleavage, with slightly higher solvent
dkie values for the diester signifying the onset of some solvent participation in assisting the nucleophilic displacement. The larger
primary dkie for the triester gives evidence for a solvent-assisted delivery of ROH in the cleavage through a more associative
mechanism. Activation parameters for each substrate in the solvents are compared, indicating that the transition from methanol
to ethanol for each substrate involves a near cancellation of the ΔΔH‡ and −TΔΔS‡ values (25 °C) so that the respective rates in
both solvents are very similar. The transition from alcohol to water produces variable effects, with ΔΔH‡ and −TΔΔS‡ values
canceling for cleavage of the triester and being additive for the mono and diester, explaining their 100−500 rate reduction in
passing from methanol to water. The rate enhancing effects of the Cu(II)-promoted leaving group assistance in all three solvents
are substantial and estimated at 1012−1015 for the monoester, 1012−1014 for the diester, and 105 for the triester relative to their
background reactions.
studies of systems incorporating metal ions that provide leaving
group assistance (LGA) in the reactions of small molecules is
documented in only a few cases.6−14
1. INTRODUCTION
The monoesters and diesters of phosphoric acid participate in a
variety of biologically important phosphoryl transfer and
hydrolysis reactions involving proteins, DNA, and RNA. The
ionization of mono- and diester derivatives of these under phy-
siological conditions is central to their suitability as
biomolecules since it serves to prevent them from crossing
biological membranes as well as to resist hydrolytic cleavage by
simple nucleophilic means.1 Triesters have no natural biological
function, but man-made versions are used commercially as
acetylcholinesterase inhibitors.2 Phosphatase enzymes, some
containing dinuclear active sites, have evolved to catalyze the
cleavage of both naturally-occurring and man-made phosphate
esters with very large rate enhancements over the uncatalyzed
solvolysis reactions.3 Various modes of metallo-catalysis4
have been discussed, such as: (1) Lewis acid activation of the
substrate via Mx+OP binding; (2) delivery of a metal-bound
hydroxide or alkoxide that serves as a nucleophile or a base; (3)
electrostatic stabilization of the anionic substrate and nucleophile/
base through binding to the (+)-charged active site and
subsequent lowering of the transition state energy of the reaction;5
and (4) stabilization of the leaving group through metal ion
coordination. As important as the latter effect is believed to be,
In the absence of catalysts, the mechanisms by which phos-
phate esters react depend on their state of O-alkylation (R) or
arylation (Ar).15 Monoesters react either by a dissociative
mechanism (DN + AN) or a concerted mechanism (ANDN) with
a loose transition state. Diesters and triesters tend to react
through concerted ANDN mechanisms (when containing an
activated LG) with progressively tighter transition states to the
limit of an associative mechanism involving a phosphorane
intermediate when substituted with a poor LG. We have com-
pared the rates and properties of the methanolysis reactions of
molecules 1−3 in the presence of Cu(II) (Scheme 1) showing
there is strong assistance of the LG departure by a closely
situated ortho-phenanthroline-bound Cu(II).16 The methanol-
yses are greatly accelerated (1014−1015 for monoester, 1014 for
diester, and 105 for triester) over the background reactions in
methanol. In all these cases, the Cu(II)-promoted LGA changes
the reaction mechanism relative to the non-LGA process, with
Received: January 10, 2012
Published: March 7, 2012
© 2012 American Chemical Society
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Article
+
added to achieve the required [ROH2 ] in solution. Typical kinetic
experiments involved preparing a buffer solution (0.4−1.2 mM)
followed by addition of the phosphate substrate (0.02 mM) in a 1 cm
path length UV cuvette. To this was added an aliquot of Cu(II) stock
solution to obtain a final concentration of 0.02 M to initiate the
reaction. Under these conditions, it was found that the substrates
existed entirely as 1:1 complexes with the Cu(II). In the case of
reasonably fast reactions (but still slower than stopped-flow time-
scale), duplicate kinetic experiments were carried out and the resulting
abs vs time traces were fit to a standard first-order exponential
equation to obtain the observed first-order rate constants (kobs). For
very slow reactions, such as the Cu(II)-promoted hydrolysis or ethano-
lysis of 2, initial rates of the reactions were obtained by fitting the first
5−10% of the abs vs time traces to a linear regression. To obtain the
kobs values, the initial rates were then divided by the expected
absorbance change (ΔAbs) if the reaction were to reach 100% com-
pletion. Separate pH/rate profiles were constructed for the Cu(II)-
catalyzed cleavages of 1−3 in the presence of 20-fold excess buffer in
water and ethanol. A typical solvent kinetic isotope experiment
involved the addition of 1 mM Cu(OTf)2 and 5 mM HOTf stock
solutions in ROD to UV cells containing either ROH or ROD so that
the final concentrations of Cu(OTf)2, phosphate ester, and buffer were
0.02, 0.02, and 0.4 mM. The kinetic competition experiments were
carried out in duplicate and the pH and pD values were measured
after the reactions were complete. (The pD values measured at the
end of the reactions were recorded as the pH meter readings (+2.54 in
the case of the ethanolysis reactions) and are not corrected for the
effect of the deuterated solvent on the reading or on the pKa of the
buffer. The actual pD value is less important since the experiments are
carried out in the extensive plateau regions of the pH/rate profiles.)
2.4. Stopped-Flow Kinetics. The Cu(II)-promoted cleavage of 1
was monitored at 390 nm in water and 415 nm in ethanol, obtaining
the rate of appearance of product using a stopped-flow apparatus
Scheme 1. Cu(II)-Promoted Methanolysis of Phosphate
Esters 1−3
solvent methanol, rather than methoxide, as the active nucleo-
phile in transition states that are more dissociative than are
found for related processes in the absence of catalysts.
Herein we report on an expanded study where the reaction
medium changes from methanol to both ethanol and water,
how these solvents affect the reaction mechanisms, and the
acceleration provided by LGA.
2. EXPERIMENTAL SECTION
2.1. Materials. Ethanol-OD (99 atom % D), trifluoromethane-
sulfonic acid (≥99%), Cu(CF3SO3)2 (98%), 2-picoline (98%), 2,6-lutidine
(99+%), 2,4,6-collidine (99%), 4-ethylmorpholine (99%), 1-methyl-
piperidine (≥98%), 1-ethylpiperidine (99%), triethylamine (99%), and
2,2,6,6-tetramethylpiperidine (99+%), were used as supplied from Aldrich.
Tetrabutylammonium ethoxide (40% in ethanol, titrated against N/2
certified standard aqueous HCl solution and found to be 1.13 M) was
purchased from Fluka. Absolute ethanol (anhydrous, degassed, and
stored under argon, freshly dispensed between kinetic experiments)
and deuterium oxide (D, 99.9%) were purchase from Fisher and CIL,
respectively. Reverse-osmosis (RO) purified water was further
deionized to 18.2 MΩ·cm using a Millipore filtration apparatus. The
following phosphate esters O-(2-[2′-phenanthrolyl]phenyl) phosphate
(1), O-(2-[2′-phenanthrolyl]phenyl) O-methyl phosphate (2), and
O-(2-[2′-phenanthrolyl]phenyl) O,O-dimethyl phosphate (3) were
synthesized and characterized as previously reported.16
thermostatted at 25.0
0.1 °C. One syringe of the stopped-flow
instrument was loaded with a 0.8 mM solution of the desired buffer in
water or ethanol containing 0.04 mM 1. The second syringe was
loaded with 0.04 mM Cu(OTf)2 in water or ethanol. When mixed, the
final concentrations of Cu(OTf)2, 1, and buffer were 0.02, 0.02, and
0.4 mM. At least five kinetic experiments were conducted at each pH
and the obtained Abs vs time traces were fitted to a standard first-order
exponential equation to give the kobs constants: these were averaged to
give the reported values in the tables. Solvent kinetic isotope experi-
ments were performed in same way as those previously described and
the pH and pD values were measured after the reaction.
2.2. General Methods. Concentration of H3O+ and CH3CH2OH2+
were determined potentiometrically using a combination glass Fisher
Scientific Accumet electrode calibrated with certified standard aqueous
buffers (pH 4.00 and 10.00) as described previously.17a The pH was
determined as −log[ROH2+]. The autoprotolysis constant for ethanol was
taken to be 10−19.1 M2 and the sspH values17b in ethanol were determined
by subtracting a correction constant of −2.5417a from the electrode
readings. The wspH values for the kinetic experiments were measured at
the end of the reactions in order to avoid any effects associated with KCl
leaching from the electrode.
2.3. General UV−vis Kinetics. The Cu(II)-catalyzed hydrolyses
and ethanolyses of 1, 2, and 3 were followed at 390 and 415 nm,
respectively, to determine the rate of appearance of Cu(II)-bound
phenoxide 4 using a UV−vis spectrophotometer with the cell thermo-
statted at 25.0 0.1 °C. Reactions were conducted in the presence of
buffers composed of various ratios of amines (2-picoline, 2,6-lutidine,
2,4,6-collidine, N-isopropylmorpholine, 1-methylpiperidine, 1-ethyl-
piperidine, triethylamine, 2,2,6,6-tetramethylpiperidine) and HOTf.
For reactions at pH 3 or lower, an appropriate amount of HOTf was
2.5. Activation Parameters. Kinetic experiments with Cu(II):1
were performed at different temperatures using a thermostatable
stopped-flow analyzer, while those for substrates Cu(II):2 and
Cu(II):3 were determined using a UV−vis spectrophotometer. The
solution temperatures were determined with a thermometer inserted
into the cell at the end of the reaction. First-order rate constants were
measured in at least duplicate at a minimum of six different tem-
peratures ranging from 15 to 40 °C for the Cu(II)-promoted hydro-
lysis or ethanolysis of 1 (both at 0.02 mM) in the presence of 0.4 mM
2,6-lutidine buffer, pH 6.9
0.2, or 2,2,6,6-tetramethylpiperidine
s
buffer, pH 11.4 0.2. Eyring plots of ln(k/T) vs 1/T provided the
s
ΔH‡ and ΔS‡ values given in Table 1. The activation parameters given
in Table 2 for substrate 2 were determined using solutions containing
0.02 mM Cu(OTf)2, 0.02 mM 2, and 1.0 mM HOTf in water (pH 3.0
0.2) and ethanol (sspH 3.0 0.2) at seven temperatures ranging
Table 1. Activation parameters, Rate Constants, and SKIE for Cleavage of Cu(II):1 in Water, Methanol,16 and Ethanol (εr = 78,
31.5, 24.3, respectively) at their pH Optima in the Plateau Region Where the Reactive Form Is the Formally Neutral Complex
a
[Cu(II):1b]0 and/or [Cu(II):1c]0
phosphate complex
solvent
kcat (s−1
max
)
ΔH‡ (kcal·mol−1
)
ΔS‡ (cal·mol−1·K−1
)
ΔG‡ (25 °C) (kcal·mol−1
)
kH/kD
[Cu(II):1b/c]
[Cu(II):1b/c]
[Cu(II):1b/c]
H2O
0.11
14.7
4.4
22.9 0.2
21.4 0.7
18.4 0.1
13.6 0.7
18.8
16.0
16.7
0.91 0.01
0.95 0.05
0.83 0.06
MeOH
EtOH
18
2
5.8 0.5
a
Data in methanol from ref 16.
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Article
Table 2. Activation Parameters, Rate Constants, and SKIE Values for Cleavage of Cu(II):2 in Water, Methanol,16 and Ethanol
(εr = 78, 31.5, 24.3, respectively) at Their pH Optima in the Plateau Region Where the Reactive Form Is the Formally Positively
a
Charged Complex [Cu(II):2b]+
phosphate complex
solvent
kcat (s−1
max
)
ΔH‡ (kcal·mol−1
)
ΔS‡ (cal·mol−1·K−1
)
ΔG‡ (25 °C) (kcal·mol−1
)
kH/kD
[Cu(II):2b]+
[Cu(II):2b]+
[Cu(II):2b]+
H2O
5.6 × 10−6
2.5 × 10−3
3.5 × 10−3
23.0 0.2
21.6 0.4
18.3 0.2
−5.8 0.5
2.3 1.1
24.7
20.9
20.8
1.22 0.01
1.01 0.04
1.29 0.03
MeOH
EtOH
−8.5 0.6
a
Data in methanol from ref 16.
Table 3. Activation Parameters, Rate Constants, and SKIE Values for Cleavage of Cu(II):3 in Water, Methanol,16 Ethanol (εr =
78, 31.5, 24.3, respectively) at their pH Optima in the Plateau Region Where the Reactive Form Is the Formally Doubly Positive
a
Charged Complex [Cu(II):3a]2+
phosphate complex
solvent
kcat (s−1
max
)
ΔH‡ (kcal·mol−1
)
ΔS‡ (cal·mol−1·K−1
)
ΔG‡ (25 °C) (kcal·mol−1
)
kH/kD
[Cu(II):3a]2+
[Cu(II):3a]2+
[Cu(II):3a]2+
H2O
1.7 × 10−5
2.0 × 10−5
7.3 × 10−5
19.1 0.1
21.6 0.5
18.4 0.3
−16.4 0.3
−7.4 1.7
−16.0 0.9
24.0
23.8
23.2
1.94 0.01
2.2 0.1
MeOH
EtOH
1.96 0.05
a
Data in methanol from ref 16.
from 15.0 to 45 °C. The activation parameters given in Table 3 for
substrate 3 were determined with solutions containing 0.02 mM
Cu(OTf)2, 0.02 mM 3, and 1.0 mM HOTf in water (pH 3.0 0.2)
and ethanol (sspH 3.0 0.2) at six temperatures ranging from 15.0 to
68.0 °C.
Scheme 2. Microscopic Ionizations for Hydrolysis of
[Cu(II):1]
3. RESULTS
3.1. Cu(II)-Promoted Hydrolysis and Ethanolysis
of 1. The pH/rate profile for hydrolysis of Cu(II):1
in Figure 1 can be fit by nonlinear least-squares methods to
[Cu(II):1b]0, this is likely the more active of the two species.
Further ionization leads to a less active (or possibly inactive)
species, [Cu(II):1d]−.
Figure 1. pH/rate profile for hydrolysis of Cu(II):1 (0.02 mM each of
Cu(II) and 1) under aqueous buffered conditions (0.4 mM amine,
0.2 mM HOTf) at 25 °C. The data are fitted by NLLSQ methods to eq 1
to give two macroscopic pKa2 and pKa3 values of 4.33 0.05 and 9.17
0.04 and a maximum rate constant (kcatmax) of 0.115 0.007 s−1; r2 =
0.9972. The solvent dkie was determined to be 0.91 0.01 in the center
of the pH 5−8 plateau region, at a measured pD = 6.8 0.2 (0.4 mM
2,6-lutidine buffer).
max
cat
2
⎛
⎝
⎞⎛
⎠⎝
⎞
⎠
+
k
K
a
[H ]
⎜
⎜
⎟⎜
⎟⎜
⎟
⎟
k
=
obs
2
+
3
+
K
+ [H ] K + [H ]
(1)
a
a
s
s
The pH/rate profile data in Figure 2 for ethanolysis of
Cu(II):1 can be fit to eq 2 derived for the model represented
schematically in Scheme 3 where [Cu(II):1]2+ undergoes two
sequential acid dissociations having macroscopic sspKa1 and sspKa2
eq 1, derived for the model given in Scheme 2 having two ion-
izable groups with pKa values of 4.33 and 9.17. Based on the
sspH/rate profile of Cu(II):1 observed earlier in methanol,16 in
the lower pH regions [Cu(II):1a]+ (or a kinetically equivalent
form where the nonbridging phosphate O− binds to Cu(II)
displacing solvent) undergoes possible microscopic ionizations in
water to form two formally neutral forms, [Cu(II):1b]0 and
[Cu(II):1c]0 which differ by coordination of a nonbridging O− to
Cu(II) with displacement of solvent. The relative proportion of
these may be influenced by solvent polarity and thus different in
the three media. However, due to the availability of both
nonbridging oxyanions to assist in the departure of the LG in
values of 2.1 and 7.7. The [Cu(II):1a]+ formed at lower spH
s
may undergo two possible microscopic ionizations to produce
[Cu(II):1b]0 and [Cu(II):1c]0. For similar reasoning as was
described above for water, [Cu(II):1b]0 probably represents
the more active species. In the less polar ethanol, further
ionization of this to form [Cu(II):1d]− (see Scheme 2) is not
observed up to at least spH 12.
s
s 1
k K
maxs 2
⎛
⎝
⎞
⎠
⎛
⎝
⎞
⎠
k
K
cat s a
1s a
⎜
⎜
⎟
⎟
⎜
⎜
⎟
⎟
k
=
+
obs
s 1
+
s 2
K + [H ]
s a
+
K + [H ]
(2)
s a
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Figure 3. pH/rate profile for cleavage of Cu(II):2 (0.02 mM of Cu(II)
and 2) under aqueous buffered conditions (0.4 mM amine, 0.2 mM
HOTf) at 25 °C. The data are fitted by NLLSQ methods to eq 3 to
give one macroscopic pKa value of 7.94 0.03 and a maximum rate
constant (kcatmax) of (5.6 0.2) × 10−6 s−1; r2 = 0.9009.
Figure 2. spH/rate profile for cleavage of Cu(II):1 (0.02 mM each of
Cu(II) and 1) in anhydrous ethanol under buffered conditions
s
(0.4 mM amine, 0.2 mM HOTf) at 25 °C. The data are fitted by
s
s
NLLSQ methods to eq 2 to give two macroscopic pKa values: 2.1
0.2 producing [Cu(II):1a]+ decomposing with a k1 = (2.1 0.2) ×
10−2 s−1 and 7.7 0.2 associated with formation of [Cu(II):1b]0 and
[Cu(II):1c]0, jointly decomposing with a maximum rate constant
(kcatmax) of 4.4 0.6 s−1; r2 = 0.9971.
Scheme 4. Microscopic Ionizations for Hydrolysis and
Ethanolysis of [Cu(II):2]
Scheme 3. Microscopic Ionizations for Ethanolysis of
[Cu(II):1]
The solvent dkie of kH/kD = 0.83 0.06 was determined in the
s
s
plateau region at an estimated pD value of 11.4
0.2,
uncorrected for D in the solvent (0.4 mM 2,2,6,6-tetramethyl-
piperidine buffer).
3.2. Cu(II)-Promoted Hydrolysis and Ethanolysis of 2.
s
Figure 4. pH/rate profile for cleavage of Cu(II):2 (0.02 mM of
s
Cu(II) and 2) in anhydrous ethanol under buffered conditions
(0.4 mM amine, 0.2 mM HOTf) at 25 °C. The data are fitted by
NLLSQ methods to eq 4 to give one macroscopic sspKa1 value of 1.05
0.01 and a maximum rate constant (kcatmax) of (3.60 0.02) × 10−3 s−1;
r2 = 0.9984.
⎛
⎝
⎞
⎠
+ 2
[H ]
+ 2
+ [H ]
dim
max
cat
⎜
⎜
⎟
⎟
log(k ) = log(k
obs
) + log
2
K /K
(3)
a
In Figure 3, the pH/rate profile for hydrolysis of Cu(II):2 is
shown. At low pH, [Cu(II):2a]2+ (Scheme 4) ionizes (not
observed) to form the reactive species [Cu(II):2b]+ (or a
chemically equivalent species where the nonbridging O− is
displaced from the Cu(II) by solvent) with an extended pH
independent region followed by its ionization (pKa 7.94) to
some inactive form, suggested to be the dimer of [Cu(II):2c]0.
That the descending portion of the profile at higher pH has a
gradient of −2 may indicate involvement of two lyoxide
molecules leading to a dimeric species with lower activity such
as was proposed previously.16 The solvent dkie in the plateau
mechanistically in Scheme 4. At low sspH, [Cu(II):2a]2+ ionizes
to produce [Cu(II):2b]+ (or its similarly charged chemical
equivalent with a solvent incorporated on the Cu(II)) which
then reacts over a pH-independent region. The solvent dkie in
s
s
the plateau region is kH/kD = 1.29 0.03 at a measured pD
value of 3.0, uncorrected for effect of D in solvent (1 mM
DOTf).
s 1
⎛
⎝
⎞
⎠
K
s a
max
cat
⎜
⎜
⎟
⎟
log(k ) = log(k
obs
) + log
s 1
+
K + [H ]
(4)
s a
region is 1.22
(1 mM DOTf).
0.01 at a measured pD value of 3.0
0.2
3.3. Cu(II)-Promoted Hydrolysis and Ethanolysis of 3.
The important species in the pH/rate profile for hydrolysis
of Cu(II):3 (Figure 5) are presented in Scheme 5. A broad
The ionization process and plateau region indicated by the sspH/
rate profile for ethanolysis of Cu(II):2 (Figure 4) are represented
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3.4. Activation Parameters. Temperature dependent
studies at the pH optima for the Cu(II)-promoted solvolyses
of 1−3 in water, methanol,16 and ethanol afforded the activa-
tion parameters that appear in Tables 1−3.
4. DISCUSSION
There are postulates that the effective dielectric constants
inside the enzyme active site resemble those of organic solvents
rather than water.19 Organic solvents like methanol and
ethanol, with dielectric constants of 31.5 and 24.320 and pro-
perties and structures closest to water, might be considered
appropriate models for the media extant in the active sites of
some enzymes,19 although this ignores specific solvation effects
such as the solvent’s H-bond and electron accepting and donating
properties. The large rate accelerations that we see for the trans-
esterifications of phosphate di- and triesters in methanol12,13,21 and
ethanol,16 are anomalous when compared with what is generally
seen in water22 but, as will be seen, there are very large accelera-
tions for the cleavages of [Cu(II):1,2,3] in water as well.
Figure 5. pH/rate profile for hydrolysis of Cu(II):3 (0.02 mM each of
Cu(II) and 3) under aqueous18 buffered conditions (0.4 mM amine,
0.2 mM HOTf) at 25 °C. The data in the pH range 2.4−7.1 are
averaged to give a rate constant of kobs = 1.7 × 10−5 s−1.
Scheme 5. Microscopic Ionizations for Hydrolysis and
Ethanolysis of [Cu(II):3]
According to X-ray diffraction studies of a close model for
the metal-bound leaving group ([Cu(II):4−], Scheme 1),
23
−
namely [(Cu(II)2:4−)2:(μ-MeCO2 )][PF6 ], the departing
phenoxy oxygen is positioned within ∼1.9 Å of the Cu(II) ion.
This is expected to be the situation in all solvents investigated.
The proposed driving force for the cleavage of the phosphates
in methanol16 stems from progressively enhancing the metal
cation’s and departing phenoxy anion’s interactions during the
transformation of [Cu(II):1,2,3] into Cu(II):4−. Thus, the
endothermicity of the P−O(LG) bond cleavage process is offset
by an exothermic binding of the transition state attributable
to the progressively enhanced Cu(II):−O(LG) electrostatic
interaction. The activation parameters and rate constants in
Tables 1−3 refer to the reactions in the plateau regions of the
pH/rate profiles where the effective nucleophile is solvent,
(either external, or metal ion−coordinated in the case of attack
on [Cu(II):1b]0, [Cu(II):2b]+, and [Cu(II):3a]2+) and the
charges of the active forms of the three Cu(II) complexes vary by
one unit each in passing from [Cu(II):1b]0 to [Cu(II):2b]+ and
−
pH-insensitive region exists between pH 2.5 and 7 where
[Cu(II):3a]2+ is likely the most active species. The solvent dkie
is kH/kD = 1.94 0.01 at an estimated pD value of 3.0 0.2 in
the plateau region (1 mM DOTf).
s
Figure 6 shows the pH/rate profile for the ethanolysis of
s
s
s
Cu(II):3 where a broad pH-insensitive region exists between
[Cu(II):3a]2+.
s
4.1. pH and pH/Rate Profiles for the Cleavage of
s
[Cu(II):1,2,3] in Water, Methanol, and Ethanol. General:
The rate constants for the solvolysis of the three complexes
were determined under conditions similar to what was used
previously for the study in methanol.16 The kinetics were deter-
mined using 1:1 mixtures of Cu(II)(triflate)2 and substrate
under the assumption that the Cu(II):substrate binding is
essentially complete. This assumption is warranted since the
rate constants obtained for this study are independent of
increasing total concentration of Cu(II) + substrate, when these
are introduced to the solution in a 1:1 mixture. In addition,
Cu(II) binding to phenanthroline systems is known to be very
strong. For example, the binding constant of phenanthroline
and Cu(II) in water24 is 1.6 × 109 M−1, and we have previously
determined that the dissociation constant of Cu(II):3 in
methanol is 2.8 × 10−7 M16. While we have not determined the
binding constants for the mono- and diesters, these are also
expected to be stronger than that for Cu(II):3 due to electro-
static interactions, particularly in ethanol. In all cases, the
product of the solvolyses is the corresponding 2[2′-phenanthrolyl]-
phenoxide:Cu(II) complex which is verified by the characteristic
UV/vis spectrum as derived from authentic material. Finally, as
is the case in methanol, there is no effect of buffer as can be
s
Figure 6. pH/rate profile for the cleavage of Cu(II):3 (0.02 mM of
s
Cu(II) and 3) in anhydrous ethanol under buffered conditions (0.4 mM
amine, 0.2 mM HOTf) at 25 °C. The data are fit by NLLSQ methods to
s
s
eq 5 to give one macroscopic pKa value of 10.8 0.1 and a maximum
rate constant (kcatmax) of (7.3 0.4) × 10−5 s−1 and k2 = (2.5 0.3) ×
10−6 s−1; r2 = 0.9907.
s
+
⎛
⎝
⎞
⎠
K
s a
[H ]
max
cat
⎜
⎟
⎟
log(k ) = log k
+ k
2
s
⎜
obs
s
+
+
K + [H ]
K + [H ]
a
(5)
s
a
s
sspH 2.5 and 9.5 followed by an ionization to produce
[Cu(II):3b]+ (Scheme 5) which reacts with lower activity in
the sspH-insensitive region. The solvent dkie was determined in
the plateau region to be 1.96 0.05 at an estimated sspD value
of 3.0, uncorrected for the effect of D (1 mM DOTf).
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judged from the pH/rate profiles which show no evidence of
breaks between different buffers.
either methanol or ethanol, even accounting for the differences
in the autoprotolysis constants. Nevertheless, considerable
ambiguity exists due to trade-offs in dielectric constant effects
and specific solvent interactions with the ground and transition
states making any rationale highly speculative.
4.1.1. [Cu(II):1]. The general pH-dependent species of
[Cu(II):1,2,3] and processes for the decomposition of each
ester are expected to be similar in the three solvents, although
the pH range over which each of their microscopic states of
ionization exist is expected to be different. The pH/rate profile
4.1.2. [Cu(II):2,3]. With [Cu(II):2] in water, no pKa1 value is
observed down to pH 1 but there is a second apparent pKa2
value for ionization of [Cu(II):2b]+ of 7.94 which is tied to a
from 2 to 12 for the hydrolysis of Cu(II):1 shown in Figure 1 is
max
bell-shaped with a k of 0.12 s−1 and two acid dissociation
following dimerization of [Cu(II):2]0. The latter value shifts to
cat
constants of sspKa2 = 4.33 and sspKa3 = 9.17 corresponding to the
transition from [Cu(II):1a]+ to two possible neutral forms
[Cu(II):1b/c]0 and transformation of [Cu(II):1b/c]0 into
[Cu(II):1d]− as in Scheme 2. In methanol, from sspH 2.5−12.5,
the profile is also bell-shaped with two sspKa2 and sspKa3 values of
7.83 and 11.8, with plateaus from sspH 2.4−4, k1 = 6.3 × 10−4 s−1,
s
a pKa2 value of 10.25 in methanol. The only observed ioniza-
s
tion of [Cu(II):2] in ethanol is sspKa1 = 1.05 forming [Cu(II):2b]+.
The rate constants for decomposition of [Cu(II):2b]+ vary by
about 2000 in the three solvents, with the lowest in water being
5.6 × 10−6 s−1, while those in methanol and ethanol are 2.5 × 10−3
and 3.5 × 10−3 s−1.
16
and from pH 8−11, k = 14.7 s−1. However, in the lowest
s
s
max
With [Cu(II):3] there is no possible acid dissociation of the
phosphate, so the only pH dependent change in charge on the
complex results from the formation of Cu(II) hydroxides or
alkoxides. No process corresponding to the conversion of
[Cu(II):3a]2+ to the Cu(II):hydroxide form [Cu(II):3b]+ is
observed from pH 1−7 in water. In methanol, the sspKa1 value is
6.05 and shifts to a value of 10.75 in ethanol. The observed rate
constants for decomposition of [Cu(II):3a]2+ in the three
solvents are very similar, being 1.7 × 10−5 s−1 in water, 2.0 ×
10−5 s−1 in methanol, and 7.3 × 10−5 s−1 in ethanol. As will be
shown, this stems from a compensation of change in both the
activation enthalpies and entropies in the three solvents.
4.2. Trends in Enthalpies and Entropies of Activation
for Decomposition of Cu(II)-Bound Phosphate Esters.
The rates of solvolytic cleavage of complex molecules depend
on the relative energy levels of the ground- and rate-limiting
transition states. Thus, a change in reaction rate brought on by
a change in solvent relate to how the medium alters these
relative energies.25 The relevant free energies for the processes
and their transfer from one solvent to another are shown in
Scheme 6, where S1 and S2 are the two solvents in question
and ΔG(°S1→S2) and ΔG(‡S1→S2) represent the free energies of
transfer of the ground and transition states between the two
solvents. The latter values are determined26 by interactions of
the solvent molecules with (1) the ground state, (2) the
transition state, and (3) other solvent molecules.
cat
s
polarity solvent ethanol, the pH/rate profile (Figure 2) is
s
sigmoidal with the hint of a sspKa1 at 2.4, a plateau from sspH 3−5
(k1 = 2.1 × 10−2 s−1), a sspKa2 of 7.70 followed by a long plateau
with k = 4.4 s−1. There is no evidence of a pKa3 value for
max
cat
s
s
ionization of [Cu(II):1] in ethanol up to sspH 12. The
difference in observed pKa3 and pKa2 values from water to
s
s
s
s
methanol and ethanol media might be a consequence of the
poorer ability of the alcohol to stabilize anion formation (as in
[Cu(II):1d]−) and/or a change in the relative amounts of
[Cu(II):1b/c]0 in the three solvents. The autoprotolysis
constants of the three solvents increase (pKauto = 14, 16.77,
17
s
s
and 19.1, respectively ) so that neutrality is at pH 7 and pH
8.4 and 9.55 respectively. Thus, in passing from methanol to
ethanol, sspKa2 ionization occurs at substantially less than
neutrality which is consistent with the lower polarity solvent
favoring the formation of the charge neutral species [Cu-
(II):1b/c]0.
The rate constants for decomposition of [Cu(II):1a]+ can be
s
compared only in methanol and ethanol, since the pH/rate
s
s
s
profiles in these solvents exhibit plateaus in the low pH
domain. The k1 value in ethanol is about 30 times greater than
in methanol (2.1 × 10−2 s−1/6.4 × 10−4 s−1), suggesting that
ethanol favors a transition state where charge is being dispersed
relative to the monocationic ground state of the complex. The
max
cat
k
rate constants for the decomposition of the formally
neutral complex [Cu(II):1b/c]0 varies by a factor of about 100
in the three solvents from 0.12 s−1 in water to 14.7 and 4.4 s−1
in methanol and ethanol. There is not a simple rationalization
for this apparently inverted order as a function of solvent
polarity; perhaps this is consistent with the proportions of
[Cu(II):1b/c]0 being different in the two alcohol solvents and/
or greater stability of the ground state of the neutral species in
water than in either alcohol since pKa2 in water is less than sspKa2 in
Equation 6 gives an expression for the ΔΔG‡ resulting from a
solvent change on the free energies of the transition and ground
states, which is further broken into the effects on ΔΔH‡ and
ΔΔS‡ as in eqs 7 and 8. For the three complexes in question,
the changes in free energies computed on
‡
‡
ΔΔG = ΔΔG
− ΔΔG
°
(S1→S2)
(S1→S2)
(6)
Scheme 6. Free Energies for Dissolution and Reaction Transition State of [Cu(II):1,2,3] and the Change in Free Energies
Induced by Changing the Solvent
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Table 4. Listing of Changes in Activation Parameters for the Decomposition of [Cu(II):1,2,3] Accompanying Changes in
Solvent from Methanol to Water and Methanol to Ethanol
CH3OH → H2O
CH3OH → CH3CH2OH
a
b
a
a
a
b
a
a
complex
ΔΔH‡
ΔΔS‡ (e.u.)
−TΔΔS‡ (25 °C) ΔΔG‡ (25 °C) ΔΔH‡
ΔΔS‡ (e.u.)
−TΔΔS‡ (25 °C) ΔΔG‡ (25 °C)
[Cu(II):1b/c]0
[Cu(II):2b]+
[Cu(II):3a]2+
1.5
1.4
−4.4
−8.1
−9
1.3
2.4
2.7
2.8
3.8
0.2
−3.0
−3.3
−3.2
−12.2
−10.8
−8.6
3.6
3.2
2.6
0.6
−0.1
−0.6
−2.5
a
b
In kilocalories per mole. In calories per kelvin mole.
‡
ΔH‡ of each reaction of roughly 3.0−3.3 kcal/mol, which is
offset by a net increase in the −TΔS‡ term of 2.6−3.6 kcal/mol;
thus the change in the overall free energy of reaction for all
three substrates does not vary appreciably at 25 °C. However,
passing from methanol to water causes wider variations of the
activation parameters in the series, increasing both ΔH‡ and
−TΔS‡ by moving NE in Figure 7 for [Cu(II):1b/c]0 and [Cu-
(II):2b]+ such that the ΔG‡ for these two reactions is raised by
2.8 and 3.8 kcal·mol−1. This accounts for the 102−103 drop in
the rates of these reactions in passing from methanol to water.
By contrast there is an approximate cancelation of these two
terms for cleavage of [Cu(II):3a]2+ in passing from methanol to
water moving NW, leading to a reduction of 2.5 kcal/mol in
ΔH‡ and an increase in the −TΔS‡ of 2.7 kcal/mol such that
the net change in ΔG‡ is only −0.2 kcal/mol.
‡
°
ΔΔH = ΔΔH
− ΔΔH
(S1→S2)
(S1→S2)
(7)
(8)
‡
‡
ΔΔS = ΔΔS
− ΔΔS
°
(S1→S2)
(S1→S2)
the basis of the changes in the activation parameters for the
decomposition of [Cu(II):1b/c]0, [Cu(II):2b]+, and [Cu-
(II):3a]2+ in passing from water to methanol and methanol
to ethanol at 25 °C are given in Table 4. This can be more
clearly seen in Figure 7 where −TΔS‡ is plotted vs ΔH‡ for the
Moving from alcohol to water induces irregular perturbations
on ΔH‡ and TΔS‡ in the series for reasons that are not obvious.
Winstein and Fainberg25 have pointed out how exceedingly
difficult it is to evaluate the effect of solvent changes such as
MeOH → water and EtOH → water even on an apparently
simple process like the solvolysis of tert-butyl chloride. While
not strictly comparable to the more complex situation of
spontaneous solvolysis of the Cu(II) complexes here with their
varying formal charges, it is clear that changes in the free energy of
solvation of the ground state (ΔΔGs°) are just as, or more,
important as those on the transition state, ΔΔGs‡.29 Given the
difficulties in separating the effect of solvent changes on ΔΔGs°
into the individual ΔΔHs° and ΔΔSs° terms, it is inappropriate to
attempt further interpretations as to the origins of the solvent
effect on the activation parameters other than to say that water
seems to be the outlier.
4.3.1. Mechanistic Picture. Cleavage of Phosphate Esters
in Solution without Catalysts. In water, the decomposition of
phosphate monoester dianions containing aryloxy leaving
groups proceeds by an apparent unimolecular route involving
a significant positive entropy and unit solvent isotope effect that
is consistent with a dissociative mechanism with little
involvement of a nucleophilic role for solvent.30 There is a
significantly more positive entropy of activation for the
solvolysis of p-nitrophenyl phosphate dianion in tert-butyl
alcohol which supports a dissociative (DN + AN) mechanism
confirming that racemization at phosphorus in this reaction is
attributed to the direct formation of meta-phosphate anion, with
no nucleophilic role for the solvent in the P−OAr cleavage.31
Kirby and Younas32 reported that the aqueous cleavage of
phosphate diesters is exceedingly slow and highly dependent on
the LG basicity. The reaction is bimolecular with hydroxide
being the active nucleophile down to pH 5 where a water-
promoted reaction was observable with leaving groups as good
as, or better than, 4-nitrophenoxy but not with poorer ones like
phenoxy or 4-methoxyphenoxy. Methanolysis of aryl methyl
phosphates involves methoxide attack on the monoanion,
Figure 7. Plot of −TΔS‡ vs ΔH‡ for the decomposition of
⧫
, respectively) in ethanol (leftmost vertical
■
▼
[Cu(II):1,2,3] ( ,
,
points), methanol (center vertical points), and water (unmarked
points) at 25 °C in the plateau regions where the active forms are
[Cu(II):1b/c]0, [Cu(II):2b]+, and [Cu(II):3a]2+. The various lines
connecting the three species are not fits, but aids for visualization.
decomposition of [Cu(II):1,2,3] in water, methanol, and
ethanol. The figure can be referred to using a compass,
where moving along the diagonal southeast (SE) in Figure 7
increases the activation ΔH‡ but reduces the TΔS‡ contribution
to ΔG‡, resulting in little effect on the reaction rate. Moving
NE increases both the enthalpy and entropy contribution,
slowing the reaction considerably. In the case of cleavage of
[Cu(II):3a]2+, moving NW from MeOH to water leads to a
decrease in ΔH‡ and more positive TΔS‡, compensating each
other to an extent that the reaction rate does not change
appreciably.
Pertinent to Figure 7 are Leffler’s and Lumry and Rajender’s
treatises discussing the enthalpy−entropy relationship for
various solvolytic and other reactions where emphasis was
put on the possible linear relationships between the two
activation parameters.27,28 These refer to related reactions or
equilibria involving modest changes in substrate or solvent,
where it is often found that the ΔH and ΔS parameters vary in
a dependent way. The Figure 7 data indicate that, for the
decomposition of [Cu(II):1b/c]0, [Cu(II):2b]+, and [Cu-
(II):3a]2+, moving from methanol (center vertical points) to
ethanol (leftmost vertical points), there is a decrease in the
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probably with a concerted departure of leaving group via an
ANDN mechanism.33
AUTHOR INFORMATION
Corresponding Author
*E-mail: rsbrown@chem.queensu.ca. Phone: 613-533-2400.
Fax: 613-533-6669.
■
Hydrolyses of dialkyl aryl phosphate triesters34 with good
leaving groups in water are subject to HO−, H3O+, and solvent
promoted reactions. For the least reactive of the tested esters
(such as the 4-nitrophenyl derivative), the base and acid wings
account for the hydrolysis over almost all the investigated pH
range except for a small deviation at ∼pH 4 that may result
from a water reaction. The methanolysis of dimethyl aryl
phosphates is methoxide promoted.35 Recent computational
studies indicate that both the hydroxide36 and methoxide37
reactions are enforced concerted with good aryloxy leaving
groups having pKa (sspKa) values <8 (m-nitrophenol in water)
or <12.3 (3,5-dichlorophenol in methanol), but stepwise with
rate-limiting formation of an anionic 5-coordinate phosphorane
intermediate when the phosphate has poorer leaving groups.
4.3.2. Decompositions of Cu(II):1,2,3 Promoted by Leaving
Group Assistance. Rate data presented here and earlier16
support the idea that positioning the Cu(II) ion close to the
leaving group’s developing oxyanion results in a loosening of
the transition state for P−O(LG) cleavage for [Cu(II):1,2,3] by
reducing the requirement for nucleophilic participation in
expelling the leaving group. Using More O′Ferrall-Jencks
diagrams, the effect of Cu(II) on the cleavage relative to the
uncatalyzed methanolysis of mono-, di-, and triesters has been
rationalized as moving the transition state earlier with respect
to P−nucleophile interaction with little change in the extent of
P−O(LG) cleavage,16 and the same is likely true in ethanol and
water. The leaving group acceleration provided by Cu(II)
coordination comes from converting the poor leaving group,
uncomplexed 2(2′-phenathrolyl)phenoxide, into a far better
leaving group.38 Extant data indicate that the βNuc for the attack
of oxyanion nucleophiles on phosphate triesters becomes smaller
as the leaving group gets better,34 and also that the kH2O for water
attack on both phosphate diester anions32 and monoester
dianions30 increases as the leaving group gets better. It follows
that, in the limit when the leaving group is very good, the effective
nucleophile will be the one having the highest concentration in
solution, namely solvent. For all three phosphate complexes in this
study, this is the case since the reactions in ethanol, methanol or
water involve only solvent attack on [Cu(II):1b/c]0, [Cu(II):2b]+,
or [Cu(II):3a]2+.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the financial assistance of
the Natural Sciences and Engineering Research Council of
Canada (NSERC), Queen’s University, and the Canada
Foundation for Innovation (CFI). In addition they acknowl-
edge helpful discussions with, and the technical assistance of,
Dr. Alexei A. Neverov.
REFERENCES
(1) Westheimer, F. H. Science 1987, 235, 1173.
(2) Hengge, A. C. Adv. Phys. Org. Chem. 2005, 40, 49.
(3) (a) Zalatan, J. G.; Herschlag, D. J. Am. Chem. Soc. 2006, 128,
1293. (b) Weston, J. Chem. Rev. 2005, 105, 2151. (c) Mancin, F.;
Tecilla, P. New J. Chem. 2007, 31, 800. (d) Aubert, S. D.; Li, Y.;
Raushel, F. M. Biochemistry 2004, 43b, 5707. (e) Morrow, J. R. Com.
Inorg. Chem. 2008, 29, 169.
(4) (a) Brown, R. S.; Lu, Z.-L.; Liu, C. T.; Tsang, W. Y.; Edwards,
D. R.; Neverov, A. A. J. Phys. Org. Chem. 2009, 22, 1. (b) Williams, N. H.;
Takasaki, B.; Wall, M.; Chin, J. Acc. Chem. Res. 1999, 32, 485.
(c) Morrow, J. Comm. Inorgan. Chem. 2008, 29, 169. (d) Mitic, N.;
́
Smith, S. J.; Neves, A.; Guddat, L. W.; Gahan, L. R.; Schenk, G. Chem.
Rev. 2006, 106, 3338.
(5) Fothergill, M.; Goodman, M. F.; Petruska, J.; Warshel, A. J. Am.
Chem. Soc. 1995, 117, 11619.
(6) Zalatan, J. G.; Catrina, I.; Mitchell, R.; Grzyska, P. K.; O’Brien,
P. J.; Herschlag, D.; Hengge, A. C. J. Am. Chem. Soc. 2007, 129, 9789.
(7) Benkovic, S. J.; Dunikoski, L. K. Jr. J. Am. Chem. Soc. 1971, 93,
1526.
(8) Hay, R. W.; Basak, A. K.; Pujari, M. P. J. Coord. Chem. 1991, 23,
43.
(9) Hay, R. W.; Basak, A. K.; Pujari, M. P.; Perotti, A. J. Chem. Soc.,
Dalton Trans. 1986, 2029.
(10) Fife, T. H.; Pujari, M. P. J. Am. Chem. Soc. 1988, 110, 7790.
(11) Bruice, T. C.; Tsubouchi, A.; Dempcy, R. O.; Olson, L. P. J. Am.
Chem. Soc. 1996, 118, 9867.
(12) Edwards, D. R.; Neverov, A. A.; Brown, R. S. J. Am. Chem. Soc.
2009, 121, 368.
(13) Neverov, A. A.; Liu, C. T.; Bunn, S. E.; Edwards, D.; White,
C. J.; Melnychuk, S. A.; Brown, R. S. J. Am. Chem. Soc. 2008, 130,
6639.
(14) Edwards, D. R.; Liu, C. T.; Garrett, G.; Neverov, A. A.; Brown,
R. S. J. Am. Chem. Soc. 2009, 131, 13738.
(15) Hoff, R. H.; Hengge, A. C. J. Org. Chem. 1998, 63, 6680.
(16) Liu, C. T.; Neverov, A. A.; Brown, R. S. J. Am. Chem. Soc. 2010,
132, 3561.
■
The data herein also indicate that there is a very large
acceleration of P−O(LG) cleavage attributable to LGA relative
to the background reactions in each solvent. While this is
quantified in only methanol16 as being 1014−1015 for the
monoester, 1014 for the diester, and 105 for the triester, the fact
that similar rate constants are observed in all solvents (changes
from little effect to no more than 500-fold rate reduction in the
case of [Cu(II):2b]+ in moving from methanol to water)
suggests that the high degree of acceleration obtained from
LGA is attainable in all three media.
The synthetic difficulties in making appropriate small
molecule systems that position the metal ion optimally to
assist in the departure of the leaving group impose serious
limitations in achieving significant LGA. Nevertheless, the
present results seem to suggest that in optimized cases, such as
enzymes where the tertiary structure controls the placement of
the metal ion relative to the departing leaving group, this mode
of catalysis could provide a significant source of acceleration.
(17) (a) Gibson, G. T. T.; Mohamed, M. F.; Neverov, A. A.; Brown,
R. S. Inorg. Chem. 2006, 45, 7891. (b) For the designation of pH in
non-aqueous solvents, we use the nomenclature recommended by
IUPAC: Compendium of Analytical Nomenclature. Definitive Rules 1997,
3rd ed.; Blackwell: Oxford, U.K., 1998. The pH meter reading for an
aqueous solution determined with an electrode calibrated with
aqueous buffers is designated as wwpH; if the electrode is calibrated
in water and the “pH” of the neat buffered methanol solution is then
measured, the term ws pH is used; and if the electrode is calibrated in
the same solvent in which the pH reading is made, then the term sspH is
used. In ethanol, ws pH −(−2.54) = pH, and since the autoprotolysis
s
s
constant of ethanol is 10−19.1, the neutral sspH is 9.6.
(18) Solvent composition = water − methanol (95−5 mol %).
(19) (a) Cleland, W. W.; Frey, P. A.; Gerlt, J. A. J. Biol. Chem. 1998,
273, 25529. (b) Simonson, T.; Carlsson, F.; Case, D. A. J. Am. Chem.
3853
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Soc. 2004, 126, 4167 and references therein. (c) Richard, J. P.; Amyes,
T. L. Bioorg. Chem. 2004, 32, 354.
(20) Harned, H. S.; Owen, B. B. The Physical Chemistry of Electrolytic
Solutions, 3rd ed.; ACS Monograph Series 137; Reinhold Publishing:
New York, 1957; p 161.
(21) (a) Neverov, A. A.; Lu, Z.-L.; Maxwell, C. I.; Mohamed, M. F.;
White, C. J.; Tsang, J. S. W.; Brown, R. S. J. Am. Chem. Soc. 2006, 128,
16398. (b) Bunn, S. E.; Liu, C. T.; Lu, Z.-L.; Neverov, A. A.; Brown,
R. S. J. Am. Chem. Soc. 2007, 129, 16238.
(22) (a) Brown, R. S. Progress in Inorganic Chemistry; Karlin, K. D.,
Ed.; John Wiley & Sons: New York, 2012; Vol. 57, p 55. (b) Brown,
R. S.; Neverov, A. A. Advances in Physical Organic Chemistry; Richard,
J. P., Ed.; Elsevier: San Diego, CA, 2007; Vol. 42, p 271.
(23) Holligan, B. M.; Jeffery, J. C.; Ward, M. D. J. Chem. Soc., Dalton
Trans. 1992, 3337.
́
(24) Sillen, L. G.; Martell, A. E. In Stability Constants; Special
Publications−Chemical Society, 1964; pp 664−665; Supp. No. 1 1971,
p 676.
(25) For a simplified introduction to the effects of solvent on
reaction rates and parameters to measure certain properties of
solvents, see: Carroll, F. A. Perspectives on Structure and Mechanism in
Organic Chemistry, 2nd ed.; John Wiley and Sons: Hoboken, NJ, 2010;
pp 337−339 and references therein.
(26) Winstein, S.; Fainberg, A. H. J. Am. Chem. Soc. 1957, 79, 5937.
(27) Leffler, J. E. J. Org. Chem. 1955, 20, 1202.
(28) Lumry, R.; Rajender, S. Biopolymers 1970, 9, 1125.
(29) Hvidt, A. Annu. Rev. Biophys. Bioeng. 1983, 12, 1.
(30) Kirby, A. J.; Varvoglis, A. G. J. Am. Chem. Soc. 1967, 89, 415.
(31) Hoff, R. H.; Hengge, A. C. J. Org. Chem. 1998, 63, 6680.
(32) Kirby, A. J.; Younas, M. J. Chem. Soc. B. 1970, 510.
(33) Liu, C. T.; Neverov, A. A.; Brown, R. S. J. Am. Chem. Soc. 2008,
130, 16711.
(34) Khan, S. A.; Kirby, A. J. J. Chem. Soc. B. 1970, 1172.
(35) (a) Edwards, D. R.; Liu, C. T.; Garrett, G.; Neverov, A. A.;
Brown, R. S. J. Am. Chem. Soc. 2009, 131, 13738. (b) Liu, T.; Neverov,
A. A.; Tsang, J. S. W.; Brown, R. S. Org. Biomol. Chem. 2005, 3, 1525.
(36) Tarrat, N. J. Mol. Struct: THEOCHEM 2010, 941, 56.
(37) Maxwell, C. I.; Liu, C. T.; Neverov, A. A.; Mosey, N. J.; Brown,
R. S. J. Phys. Org. Chem. 2011, DOI: 10.1002/poc.1938.
s
s
(38) The pKa of 2(2′-phenanthrolyl)phenol drops from 16.17 to
0.40 and methanol when coordinated to Cu(II).16 While the
equivalent pKa values are not known in water of ethanol, it is certain
that Cu(II) complexation will substantially acidify the phenol.
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dx.doi.org/10.1021/ic300059e | Inorg. Chem. 2012, 51, 3846−3854