Trifunctional metal ion-catalyzed solvolysis: Cu(II)-promoted methanolysis of N,N-bis(2-picolyl) benzamides involves unusual lewis acid activation of substrate, delivery of coordinated nucleophile, powerful assistance of the leaving group departure

Article abstract of DOI:10.1021/ic301454y

The methanolyses of Cu(II) complexes of a series of N,N-bis(2-picolyl) benzamides (4a-g) bearing substituents X on the aromatic ring were studied under ^s _s pHcontrolled conditions at 25 °C. The active form of the complexes at neutral s s pH has a stoichiometry of 4:Cu(II): (-OCH ₃)(HOCH₃) and decomposes unimolecularly with a rate constant k_x. A Hammett plot of log(k_x) vs σ_x values has a ?_x of 0.80 ± 0.05. Solvent deuterium kinetic isotope effects of 1.12 and 1.20 were determined for decomposition of the 4-nitro and 4-methoxy derivatives, 4b:Cu(II):( ^-OCH₃)(HOCH₃) and 4g:Cu(II):( ^-OCH₃)(HOCH₃), in the plateau region of the ^s _s pH/ log(k_x) profiles in both CH ₃OH and CH₃OD. Activation parameters for decomposition of these complexes are ΔH^≠ = 19.1 and 21.3 kcal mol ^-1 respectively and ΔS≠ = -5.1 and -2 cal K^-1 mol^-1. Density functional theory (DFT) calculations for the reactions of the Cu(II):(^-OCH3)(HOCH3) complexes of 4a,b and g (4a, X = 3,5-dinitro) were conducted to probe the relative transition state energies and geometries of the different states. The experimental and computational data support a mechanism where the metal ion is coordinated to the N,N-bis(2-picolyl) amide unit and positioned so that it permits delivery of a coordinated Cu(II):(^-OCH₃) nucleophile to the C=O in the rate-limiting transition state (TS) of the reaction. This proceeds to a tetrahedral intermediate INT, occupying a shallow minimum on the free energy surface with the Cu(II) coordinated to both the methoxide and the amidic N. Breakdown of INT is a virtually barrierless process, involving a Cu(II)-assisted departure of the bis(2-picolyl)amide anion. The analysis of the data points to a trifunctional role for the metal ion in the solvolysis mechanism where it activates intramolecular nucleophilic attack on the C=O group by coordination to an amidic N in the first step of the reaction and subsequently assists leaving group departure in the second step. The catalysis is very large; compared with the second order rate constant for methoxide attack on 4b, the computed reaction of CH₃O^- and 4b:Cu(II):(HOCH₃)₂ is accelerated by roughly 2.0 × 10¹⁶ times.

Full text of DOI:10.1021/ic301454y

Article
pubs.acs.org/IC
Trifunctional Metal Ion-Catalyzed Solvolysis: Cu(II)-Promoted
Methanolysis of N,N‑bis(2-picolyl) Benzamides Involves Unusual
Lewis Acid Activation of Substrate, Delivery of Coordinated
Nucleophile, Powerful Assistance of the Leaving Group Departure
Mark A. R. Raycroft, Christopher I. Maxwell, Robyn A. A. Oldham, Areen Saffouri Andrea,
Alexei A. Neverov, and R. Stan Brown*
Department of Chemistry, Queen’s University, Kingston, Ontario, Canada K7L 3N6
S
* Supporting Information
ABSTRACT: The methanolyses of Cu(II) complexes of a
series of N,N-bis(2-picolyl) benzamides (4a−g) bearing
s
s
substituents X on the aromatic ring were studied under pH-
controlled conditions at 25 °C. The active form of the
s
s
complexes at neutral pH has a stoichiometry of 4:Cu(II):
(−OCH3)(HOCH3) and decomposes unimolecularly with a
rate constant kx. A Hammett plot of log(kx) vs σx values has a
ρx of 0.80 0.05. Solvent deuterium kinetic isotope effects of 1.12 and 1.20 were determined for decomposition of the 4-nitro
and 4-methoxy derivatives, 4b:Cu(II):(−OCH3)(HOCH3) and 4g:Cu(II):(−OCH3)(HOCH3), in the plateau region of the sspH/
log(kx) profiles in both CH3OH and CH3OD. Activation parameters for decomposition of these complexes are ΔH⧧ = 19.1 and
21.3 kcal mol−1 respectively and ΔS⧧ = −5.1 and −2 cal K−1 mol−1. Density functional theory (DFT) calculations for the
reactions of the Cu(II):(−OCH3)(HOCH3) complexes of 4a,b and g (4a, X = 3,5-dinitro) were conducted to probe the relative
transition state energies and geometries of the different states. The experimental and computational data support a mechanism
where the metal ion is coordinated to the N,N-bis(2-picolyl) amide unit and positioned so that it permits delivery of a
coordinated Cu(II):(−OCH3) nucleophile to the CO in the rate-limiting transition state (TS) of the reaction. This proceeds to
a tetrahedral intermediate INT, occupying a shallow minimum on the free energy surface with the Cu(II) coordinated to both
the methoxide and the amidic N. Breakdown of INT is a virtually barrierless process, involving a Cu(II)-assisted departure of the
bis(2-picolyl)amide anion. The analysis of the data points to a trifunctional role for the metal ion in the solvolysis mechanism
where it activates intramolecular nucleophilic attack on the CO group by coordination to an amidic N in the first step of the
reaction and subsequently assists leaving group departure in the second step. The catalysis is very large; compared with the
second order rate constant for methoxide attack on 4b, the computed reaction of CH3O− and 4b:Cu(II):(HOCH3)2 is
accelerated by roughly 2.0 × 1016 times.
are small molecule systems for the cleavage of carboxamides6
where the leaving group is not activated. These are notoriously
1. INTRODUCTION
The usual ways that metal ions promote solvolytic reactions of
carboxylate esters and amides, as well as neutral and anionic
inert to solvolysis of the >N−CO because of the inherent
resonance stability which shields the substrate from nucleo-
organophosphorus esters comprise the following: (1) electro-
philic attack, and also because of poor leaving group ability of
philic Lewis acid activation of the substrate through X=O or
the amide anion from the subsequently formed tetrahedral
X=S coordination, where X = C or P; (2) intramolecular
intermediates.7 Because the interaction of neutral amides and
delivery of metal-coordinated lyoxide nucleophiles; (3) electro-
positively charged metal ions or their complexes in solution,
static stabilization of the transforming substrate-nucleophile
particularly water, is weak, catalyzed solvolysis is depressed
species; and (4) electrophilic assistance of the departure of the
further6e unless the substrate possesses some mode of
leaving group (LGA).1−4 The first three of these roles have
been demonstrated with several types of substrates, and
attraction such as a pronounced soft-soft interaction,8 a residue
acting as an attractive site,9 or attached ligands6b that positions
particularly for the decomposition of poorly reactive anionic
the metal ion close to the scissile bond. Even so, amides with
phosphate mono- and diesters or neutral phosphate triesters as
normal amine leaving groups are generally not very active
well as carboxylate esters and amides. In most of these cases,
because of the reluctance of their departure from the
metal binding ligands are attached to the substrate to position
tetrahedral intermediate unless they have a low pKa (e.g.,
the metal ion close to the X=O or X=S unit to optimize Lewis
acid activation. Metal ion catalysis for the decomposition of
amides, particularly peptides in metallo-peptidase enzymatic
Received: July 5, 2012
Published: September 12, 2012
systems, is also of general importance,5 but less well-described
© 2012 American Chemical Society
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imidazole or anilide) or there is a physical effect such as release
of strain (as in distorted amides10 and lactams11).
4a−g under sspH-controlled22 conditions along with supporting
density functional theory (DFT) computations. This study
complements and expands the communication of the
methanolysis of 1:Cu(II),12 presenting additional details of
the mechanism by providing the Hammett linear free energy
relationship of log(kx) vs σx for cleavage of various 4:Cu(II),
solvent kinetic isotope effects (SKIE) and activation parameters
for the cleavage of representative examples 4b:Cu(II) and
4g:Cu(II), as well as a comparative DFT computational study
for the cleavage of 4a:Cu(II), 4b:Cu(II), and 4g:Cu(II).
Recently we communicated a mechanistic study12 of an
unusual methanolysis reaction of the Cu(II)-complex of N,N-
bis(2-picolyl) acetamide, 1, the products of which are methyl
acetate and Cu(II):N,N-bis(2-picolyl)amine. This reaction was
the subject of an early report by Houghton and Puttner13 some
40 years ago describing the methanolysis of some N-acyl
derivatives of N,N-bis(2-picolyl) amine in the presence of
Cu(II). Subsequent physical studies with such amides,14−16 the
demonstration of their synthetic utility17 as well as the recent
reports on the methanolysis of metal complexes of secondary
amides18 and demonstration of mild methanolytic cleavage of a
special class of amides, 2,19 prompted us to expand a program20
investigating the scope and importance of metal ion-promoted
leaving group assistance (LGA) during the alcoholysis
reactions.
2. RESULTS
a. Kinetics. The Cu(II)-promoted methanolysis of coordi-
s
nated N,N-bis(2-picolyl) acetamide (1) exhibits a kinetic pKa
s
s
s
of 6.5 leading to a broad pH-insensitive region from 7 to 10
where the complex is in its basic active form, 1:Cu(II):
(−OCH3)(HOCH3).12 With the expectation that the reactivity
s
of 4:Cu(II) has a similar sensitivity to pH as 1:Cu(II), their
s
s
s
methanolyses were studied at three pH values in the 7−8
plateau region of the sspH/log(kx) profile under buffered
conditions (excess 2,4,6-collidine buffer) in the presence of
excess Cu(II) (three concentrations of 1.0, 1.5, and 2.0 mM) to
ensure that 4 is completely bound to Cu(II) during the
reaction. The three rate constants (kobs) for unimolecular
decomposition of each complex, corrected for buffer and excess
Cu(II) effects, were averaged to obtain kx values. According to
the mechanism depicted in Scheme 1, ionization of 4:Cu(II):
(HOCH3)2 generates the active form 4:Cu(II):(−OCH3)-
(HOCH3) which spontaneously decomposes. Given in Table
1 are the various kx rate constants for the decomposition of
Our initial observation6e of where this effect might be
operative was during the methoxide reaction of the (H3N)5Co-
(III)-complex of acetyl imidazole (3); there the second order
Table 1. Hammett Substituent Constants (σx) and Average
Rate Constants (kx) for the Decomposition of 4a−g:Cu(II):
(−OCH3)(HOCH3) at 25.0 °C, Determined from Data at
rate constant for methoxide attack (kMeO = 4.69 × 107 M−1
−
s
s
s−1) was 4 orders of magnitude higher than that for acetyl
Three pH Values between 7 and 8
imidazole itself (kMeO = 7.9 × 103 M−1 s−1). The large
−
a
substrate
σx
104 kx (s−1
)
acceleration was surmised to result in part from (H3N)5Co-
(III)-activation of the acyl group by reducing the imidazole’s
resonance donation, in part from a methanolic medium induced
electrostatic enhancement of the reaction of oppositely charged
substrate and nucleophile and partly from the reduction in pKa
of the conjugate acid of the leaving group (10 for H-Im-
Co(III)(NH3)5 vs 14 for H-Im)21 as a consequence of LGA. In
the case of 1:Cu(II), the metal ion enacted a trifunctional role12
(which we term as trifunctional catalysis) to accelerate the
methanolysis by (1) positioning the metal ion close to the
amide N, binding to its lone pair to reduce amidic resonance;
(2) binding and intramolecularly delivering a coordinated
methoxide to the CO unit; and (3) electrophilically assisting
the departure of the leaving group amide anion.
4a
4b
4c
4d
4e
4f
1.42
0.78
193 40
53
58
2
6
0.71
0.23
24.8 0.7
0.0
11
11
1
2
−0.17
−0.27
4g
8.3 0.5
a
Determined as the average of three corrected rate constants (kobs) for
decomposition of 4a−g:Cu(II):(−OCH3)(HOCH3) in the plateau
s
s
rection in the pH/log(kx) profile between 7 and 8.
4a−g:Cu(II):(−OCH3)(HOCH3) in the pH/log(kx) plateau
region from which a linear free energy relationship was
constructed, correlating log(kx) with the Hammett substituent
constants, σx, as shown in Figure 1.
s
s
Herein we report experimental details of the Cu(II)-
promoted cleavage of a series of N,N-bis(2-picolyl) benzamides
s
Scheme 1. Simplified Scheme for the pH Dependent Decomposition of 4:Cu(II):(−OCH3)(HOCH3) to Form Cu(II):N,N-
s
bis(2-picolyl)amine (Cu(II):DPA) and the Corresponding Methyl Benzoate (MB)
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and energetic determinations for all intermediates and
transition states were performed using the unrestricted
B3LYP23 functional employing the IEFPCM24 continuum
solvation model as implemented in the Gaussian 09 program.25
The 6-31G(d,p) basis set was used for C and H; the 6-31+
+G(d,p) basis set was used for O and N; and the LANL2DZ26
pseudopotential was used for Cu(II). Frequency calculations
were conducted on optimized structures to determine free
energy values at 298 K as well as to characterize intermediates
and transition states. The lowest energy pathway for each
amide is shown in Figure 2 and relevant structural data and
activation parameters are shown Tables 3 and 4.
Figure 1. Hammett plot of log(kx) vs σx for the Cu(II)-promoted
cleavage of 4a−g (5 × 10−4 M) in methanol at 25 °C in the plateau
s
s
region (7−8) of the pH/log(kx) profile. The line through the data is
3. DISCUSSION
generated from a linear regression to provide ρx = 0.80 0.05; r2 =
a. Lyoxide-Promoted Kinetics of Acyl Transfer. We first
consider what is known about base-promoted acyl transfer from
amides to solvent in the absence of metal-ion catalysts. The
kinetics for alkaline hydrolysis of benzamides and tolua-
mides7,27 and those for anilides28 as well as the basic
methanolysis of anilides and benzamides29 have received
attention. In Scheme 230 is the general picture where there are
0.9844 (7 data).
b. Activation Parameters and Solvent Kinetic Isotope
Effects. Experiments were carried out at five different
s
s
temperatures in the plateau region of the pH/log(kx) profiles
for substrates 4b:Cu(II):(−OCH3)(HOCH3) and 4g:Cu(II):
(−OCH3)(HOCH3). The respective Eyring plots at pH 7.0
s
s
0.2 and 7.1 0.2 are shown in Supporting Information, Figures
Scheme 2. Generalized Mechanism for the Base-Promoted
Acyl Transfer of Amides
1S and 2S, while the corresponding activation parameters are
given in Table 2. Also included in Table 2 are solvent
deuterium kinetic isotope effects (SKIE) determined in
triplicate for cleavage of 4b:Cu(II):(−OCH3)(LOCH3) and
4g:Cu(II):(−OCH3)(LOCH3) in CH3OL (L = H, D) buffered
s
with 2,4,6-collidine, (4b:Cu(II):(−OCH3)(LOCH3) pH = 7.1
s
0.2, pD = 7.2 0.2; 4g:Cu(II):(−OCH3)(LOCH3) pH =
s
s
s
s
s
s
7.4 0.2, pD = 7.4 0.2). The pD values were measured at
s
s
s
s
the end of the reactions in the same fashion as for pH; these
two primary steps for acyl transfer involving nucleophilic attack
are not corrected for the effect of the deuterated solvent on the
−
sspKa of the buffer or on the electrode readings. Since we are
to form an anionic tetrahedral intermediate (TO ), followed by
s
its breakdown to form the corresponding amine and
carboxylate (if hydrolysis) or ester (if alcoholysis where R′ =
alkyl or aryl). The latter step poses most of the interesting
kinetic behavior since the departure of the leaving group often
requires assistance from specific or general acids and bases.
Schowen31 reports that the kinetic rate law for basic hydrolysis
of anilides has first and second order terms in [−OH], and the
rate-determining step changes with base concentration. Some
simplification of the kinetics is seen in the methanolysis of
anilides where the attacking CH3O− group precludes lyoxide
dealing with an extended plateau region of the pH/log(kx)
s
s
s
profiles, the actual pD values are less important since the rate
constants in deuterated and proteated solvent are determined
in the plateau region.
c. DFT Computations. The cleavage reactions of the
Cu(II):(−OCH3)(HOCH3) complexes of 4a,b,g were modeled
using DFT to ascertain detailed mechanistic information and to
correlate the computed energies of the transition states with
their kinetic data. The starting ground state for each of the
calculated pathways was the 5-coordinate monocationic
complex [4:Cu(II):(−OCH3)(HOCH3)]+. The primary goal
of the calculations was to determine differences in relative free
energies of the various transition states for each of the three
substrates and their intermediates along the reaction pathway.
Although the absolute values of the free energies of activation
will be affected by the omission of explicit molecules of
solvation, these were not included under the assumption that
solvation should be similar for each substrate, and thus not
important in determining the differences in energies between
the same states of the three substrates. Geometry optimizations
−
deprotonation of TO (R′ = CH3) so the kinetics are simply
first order in [−OCH3]. SKIE data for methanolysis indicate
general acid assistance by the solvent for departure of the
leaving group and, in certain cases, added buffers such as
substituted phenols can also exert general assistance of the
departure of the poor leaving group. Substituent effects exerted
by Y-groups on the departing anilide (NRArY) show an
increase in the amount of negative charge on the leaving group
in the transition state for its departure as the substituents
become more electron withdrawing (ρy ∼ 0 for electron donors
Table 2. Activation Parameters, Rate Constants, and SKIE Values for Cleavage of [4b:Cu(II):(−OCH3)(HOCH3)]+ and
[4g:Cu(II):(−OCH3)(HOCH3)]+ in Methanol at sspH 7.0 0.2 and 7.1 0.2, Respectively, Determined in the Plateau Region
s
s
of their pH/log(kx) Profiles
substrate
kx (s−1
3.9 × 10−3
5.7 × 10−4
)
ΔH⧧ (kcal mol−1
)
ΔS⧧ (cal mol−1 K−1
−5.4 0.6
)
ΔG⧧ (25 °C) (kcal mol−1
)
kH/kD
[4b:Cu(II):(−OCH3)(HOCH3)]+
[4g:Cu(II):(−OCH3)(HOCH3)]+
19.1 0.2
21.3 0.3
20.7
21.8
1.12 0.01
1.20 0.02
−2
1
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Figure 2. DFT-computed reaction pathway for the cleavage of the Cu(II):(−OCH3)(HOCH3) complexes of 4a (black); 4b (blue); and 4g (red) in
methanol. All free energy values are to scale and are reported in kcal mol−1 at 298 K relative to the GS structure.
a
Table 3. Structural Data for DFT-Calculated Structures for the Cu(II):(−OCH3)(HOCH3) Complexes of 4a,b,g
Cu(II):(−OCH3)
(HOCH3) complex of
b
4a,b,g
(Py)N-Cu(II)-N(Py)
χN
Cu(II)-Ntrig (Å)
Cu(II)-OCH3 (Å)
CH3O−C(O) (Å)
Ntrig-C(O) (Å)
GS
4a
105.0°
105.8°
104.5°
105.5°
108.1°
108.1°
107.7°
110.2°
116.4°
116.7°
114.4°
129.0°
125.3°
120.9°
158.7°
161.6°
150.1°
149.6°
154.1°
152.6°
132.9°
132.9°
132.6°
136.5°
133.1°
132.7°
132.6°
129.2°
130.1°
130.7°
131.8°
2.73
2.76
2.73
2.67
2.05
2.05
2.03
2.03
2.02
2.01
2.01
1.99
1.99
1.99
2.01
1.97
1.84
1.84
1.84
1.84
1.98
1.99
2.00
1.99
2.15
2.12
2.10
2.27
2.23
2.16
2.38
3.43
3.52
3.40
3.26
1.80
1.78
1.73
1.69
1.53
1.54
1.55
1.45
1.47
1.50
1.47
1.38
1.38
1.39
1.38
1.54
1.56
1.59
1.57
1.64
1.66
1.68
1.91
1.88
1.83
1.82
4b
4g
1:Cu(II)
TSNu
4a
4b
4g
1:Cu(II)
INT
4a
4b
4g
TSClv
4a
4b
4g
1:Cu(II)
P+
MB
4a
4b
4g
1.33
1.34
1.35
a
b
Structural information for 1:Cu(II):(−OCH3)(HOCH3) is taken from ref 12. χN corresponds to the C−C−N-C(O) dihedral and is a measure of
the trigonal nitrogen’s pyramidalization that varies from 180° (sp2 hybridization) and 120° (sp3 hybridization). (Winkler, F. K.; Dunitz, J. D. J. Mol.
Biol. 1971, 59, 169.)
like p-OCH3 in the anilide ring, but ρy = 2.9 for withdrawers
such as m-NO2 or p-NO2).
refer to a discrete kinetic step, but a complex term derived from
Scheme 2 where kx = k1[−OH]k2/(k−1 + k2). Particularly
relevant to the present work are the reports of Broxton and
Deady on the basic methanolysis of N-methylbenzanilides29f
and N-aryl-N-phenylbenzamides29c (5). Rate constants for
methanolysis of compounds substituted in the benzoyl ring
(i.e., X; Y = H) correlate well with σx (ρx = 1.76 (5a), 1.95
(5b)), indicative of a mechanism common to tertiary
benzamides in methanol where the rate-limiting step is a
solvent-assisted departure of the leaving group. This is generally
confirmed by the Hammett plot of the rate constants for
As we deal here with the cleavage of benzamides, it is
relevant that Meloche and Laidler27c reported a Hammett ρ =
0.7 for hydroxide attack on some substituted benzamides at 100
°C in water. However, later 18OC exchange studies27e
indicated that the −OH-promoted hydrolyses of benzamide,
and to a lesser extent, N-methyl benzamide, but apparently not
the tertiary N,N-dimethyl benzamide, suffer reversible for-
−
mation of TO (Scheme 2). Thus, Meloche’s and Laidler’s
Hammett ρ-value, and related activation parameters, do not
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all of which show development of negative charge on the
benzoyl group in the transition states. However, in addition to
the solvent, nucleophile and substrate differences, none of the
mechanisms operative in those systems is directly comparable
to the mechanism for the decomposition of 4:Cu(II):
(−OCH3)(HOCH3). This is made clearer by the additional
information for the decomposition of the Cu(II) complexes
derived from the computational data presented below.
c. DFT Computational Studies. The lowest energy
pathways computed for the cleavage reactions of 4a,b,g:Cu-
(II):(−OCH3)(HOCH3) are shown in Figure 2 with the
relevant structural data and activation parameters given in
Tables 3 and 4. Several possible ground state structures were
calculated, and the lowest energy complex found was the
trigonal bipyramidal Cu(II):(−OCH3)-containing structure
labeled as GS having the pyridine moieties and methoxide
occupying equatorial positions. In GS, the aryl ring is coplanar
with the adjacent CO bond. All free energy values are
reported relative to the free energy of this structure. The amide
nitrogen geometry in this structure suggests a degree of
Cu(II)−Namidic interaction, however to a lesser extent than is
shown with the corresponding acyl structure, 1:Cu(II):
(−OCH3)(HOCH3) as judged from the Cu(II)−Namidic
distance12 (2.73−2.76 Å vs 2.67 Å).
Table 4. DFT-Calculated Activation Parameters for the
Cleavage of the Cu(II):(−OCH3)(HOCH3) Complexes of
4a,b,g (298 K, 1 atm)
a
structure
ΔG⧧, kcal mol−1 ΔH⧧, kcal mol−1 ΔS⧧, cal mol−1 K−1
TSNu
4a
14.7
15.8
16.7
13.5
15.6
16.0
13.8
15.7
16.0
11.8
12.5
13.2
11.2
12.2
13.4
11.2
11.8
13.5
−9.8
4b
4g
4a
4b
4g
4a
4b
4g
−11.1
−11.9
−7.8
−11.3
−8.7
−9.1
−13.0
−8.2
INT
TSClv
a
All energies are relative to the respective GS structure.
compounds 5 substituted on the anilide ring (i.e., Y; X = H)
which correlates well with σy (ρy = 2.5 (5a), 2.82 (5b)) in
methanol, the large value of ρy being indicative of rate-limiting
solvent-assisted departure of the LG (k2(MeOH) in Scheme 2)
where negative charge is building up on the anilide. Additional
data from Broxton, Deady, and Rowe29c indicate that, as the
amine leaving group gets better, k2 increases and the rate-
limiting step becomes nucleophilic attack.
Nucleophilic attack proceeds via closure of the amidic O
C---−OCH3:(Cu(II)) bond distance in TSNu, and is associated
with free energies of 14.7 kcal mol−1 (4a), 15.8 kcal mol−1 (4b),
and 16.7 kcal mol−1 (4g). The OC---−OCH3 interatomic
distances given in Table 3 for TSNu vary from 1.80 Å (4a) to
1.73 Å (4g), indicating tighter transition states and higher
transition state energies with more electron-donating aryl
substituents. For each 4 tested, there is a larger degree of
Cu(II)−Namidic interaction during nucleophilic attack, as
indicated by a shortening of that bond (from 2.73−2.76 Å to
2.03−2.05 Å) and an increase in nitrogen pyramidalization (χN
decreases from ∼150−154° to 132.6−132.9°; Table 3). The
TSNu structure leads to a single tetrahedral intermediate
structure INT, which occupies a shallow minimum on the
free energy surface. This can be contrasted with the previously
reported12 DFT-calculated mechanism for the breakdown of
the acetyl derivative 1:Cu(II):(−OCH3)(HOCH3) which was
found to involve two sequential tetrahedral intermediates
separated by a transition state that largely involved the
rearrangement of the ligands about the Cu(II). Such a
rearrangement of the ligands around the Cu(II) in 4 does
not appear to be operative, as there is a single INT that rapidly
progresses to product through TSclv where the latter involves
departure of the amide anion coordinated to Cu(II). This may
be a consequence of a destabilization of the equivalent planar
Cu(II) intermediate (Structure INT3 in ref 12) because of the
unfavorable steric interaction caused by the bulkier aryl
benzamide moiety relative to the smaller acetamide. The INT
breakdown is virtually barrierless, involving a shortening of the
Cu(II)-trigonal N bond distance by 0.02−0.03 Å to 1.99 Å for
4b,g and 4a with concurrent planarization of the Cu(II)
(opening of the (Py)N−Cu(II)−N(Py) angle). The trigonal
N−C(O) interatomic distance lengthens in TSclv, varying
from 1.91 Å (4a) to 1.83 Å (4g), indicative of later transition
states for benzamides containing more electron withdrawing
groups. The square planar product structure (P) follows this
transition state; the (Pyr-CH2)2N−---Cu(II) departs without N-
protonation, but having departed, is assumed to be rapidly
protonated under the reaction conditions.
b. Kinetics of Decomposition of 4:Cu(II):(−OCH3)-
(HOCH3). The kx data in Table 1 for the reaction of 4a−g in
the presence of Cu(II) ion refer to the unimolecular
decomposition of 4:Cu(II):(−OCH3)(HOCH3). The exper-
imental activation parameters for the p-nitro and p-methoxy
derivatives [4b:Cu(II):(−OCH3):(HOCH3)]+ and [4g:Cu(II):
(−OCH3)(HOCH3)]+ are, respectively, ΔH⧧, 19.1 and 21.3
kcal mol−1, and ΔS⧧, −5.4 and −2 cal mol−1 K−1. The reactions
proceed readily at 25 °C, t1/2 = ∼2 and 19 min respectively,
indicating that the Cu(II) has a profound effect. A simple
calculation indicates that the apparent second order rate
constant for the reaction of CH3O− with 4b:Cu(II):(HOCH3)2
is 1.0 × 108 M−1 s−1. This value is at least 2.0 × 1016 larger than
−
the kMeO for attack of methoxide on 4b in the absence of the
Cu(II).32
As was the case for the previously reported reaction of
1:Cu(II):(−OCH3)(HOCH3),12 the activation parameters and
D
SKIE data of kxH/kx of 1.1−1.2 observed here for
decomposition of [4b:Cu(II):(−OCH3)]+ and [4g:Cu(II):
(−OCH3)(HOCH3)]+ support a process of substantially rate-
limiting, intramolecular nucleophilic attack of a Cu(II)-
coordinated methoxide on the N-bound >N−CO(Ar) unit.
The Hammett ρx of 0.80 suggests a transition state where some
negative charge is building up on the aromatic ring, but not as
much as in the case of the methoxide-promoted methanolysis
of the tertiary benzanilides, 5. The fact that the plot in Figure 1
is linear, with no sign of an upward or downward break,
suggests that there is no change in mechanism or rate-limiting
step in passing through the members of series 4a−g. The
Hammett value can be compared to the ρx for attack of
hydroxide on substituted methyl benzoate esters (2.233a),
hydroxide on benzamides (0.727b), and methoxide on methyl
aryl carbamates (2.15, 1.733b) or benzanilides (1.76,29f 1.9529c
)
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d. Computed Hammett Plot. The computed mechanisms
for all substrates reveal that the rate-determining process is the
intramolecular nucleophilic attack of the Cu(II)-coordinated
methoxide on the CO unit. Where a direct comparison can
be made for [4b:Cu(II):(−OCH3)(HOCH3)]+ and [4g:Cu(II):
(−OCH3)(HOCH3)]+, the computed free energies (Table 4)
are less than those determined experimentally by 3.4 and 4.6
kcal mol−1. The differences are likely due to the absence of
explicit solvent−solute interactions in the calculated process,
specifically in desolvating the nucleophilic methoxide, and
resolvating the developing C−O− in TSNu. Since all the
substrates should experience similar desolvation/resolvation, or
ones that change regularly with the electron withdrawing nature
of the substituent on Ar, we assume these can be omitted
leaving the differences in free energy of activation of the three
computed species as being more representative of the process
at hand. Indeed, the DFT calculated free energies for the
structures are used to construct a Hammett Plot (Supporting
Information, Figure 2S) with ρx = 0.84 0.16, which is the
same as the experimental value of 0.80 0.05.
hypothesis that, for enzyme-catalyzed acyl transfer reactions of
peptides, a portion of the exothermicity of substrate binding is
utilized in a productive way by the enzyme to destabilize and
thereby activate the scissile substrate bond as the transition
state for the acyl transfer reaction is approached.38
A subsequent important role of the metal ion in this system
is to assist the departure of the LG via Lewis acid coordination
to the developing amide anion, thereby lowering the transition
state energy for the cleavage of the tetrahedral intermediate.
This is an additional important aspect for a two-step, metal ion-
catalyzed process where the metal ion must promote both the
addition and the breakdown steps, fulfilling a multifunctional
role. This sort of interaction is likely to be an important
phenomenon in enzyme-catalyzed hydrolytic or alcoholytic
cleavage of substrates with poor leaving groups where
electrophilic assistance must be given to enhance both
nucleophilic attack and LG departure.
According to the principles of enzyme catalysis first
enunciated by Pauling,39 “the enzyme has a configuration
complementary to the activated complex, and accordingly has
the strongest power of attraction for the activated complex.”
Extending this leads to the widely held notion that good
catalysts bind transition states stronger than they bind ground
states. Furthermore, for any catalyst promoting a multistep
reaction, each of the steps must be lowered in energy to achieve
the overall high rates for the catalytic reaction. Zhang and Houk
have recently analyzed40 a large number of enzymatic systems,
concluding that the very best catalytic systems have a transition
state binding energy well in excess of what can be achieved by
noncovalent interactions. That proficiency arises from addi-
tional covalent effects such as heavy atom- and H-bond
formation, and strong interactions of cofactors such as metal
ions with transforming substrates that develop between the
enzyme (catalyst) and transition state, thereby altering the
mechanism from what is seen in the absence of catalyst. It is an
interesting observation that this sort of covalent bonding is
manifested in the way the Cu(II) binds the transition states for
the two-step solvolysis reaction described herein, and in other
systems we have reported for efficient alcoholysis of
phosphorothioates41 and thioamides42 promoted by a simple
palladacycle. These types of interactions should be manifested
in other systems where ligands are bound to departing groups
so that a metal ion can facilitate the solvolytic cleavage of
amides, esters, carbamates, phosphates, phosphoramidates, and
sulfates in such a way that they may prove more generally useful
in synthetic applications.
4. CONCLUSIONS
The present, and earlier, studies12−17 indicate that poorly
reactive amides having OC−N(Lig)2 units that bind metal
ions such as Cu2+ become unusually reactive toward
methanolysis of their metal-complexes at room temperature
and neutral sspH. The close positioning of Cu(II) to the amidic
N of a N−CO unit permits several catalytic roles for the
metal ion. Some of these are common to metal ion-catalyzed
solvolytic cleavage of other systems, such as (1) positioning a
nucleophilic lyoxide and a bound substrate to a metal ion
closely enough for reaction; (2) reduction of the pKa of a metal-
bound solvent molecule so that it becomes the preferred
nucleophile; and (3) electrostatic stabilization by the metal ion
of a developing anionic TSNu. The present system exhibits
unusual modes of the Cu(II) interaction with the TSNu that are
rarely observed in metal ion-catalyzed solvolyses, possibly
because of the difficulty in positioning the metal ion, in small
molecule examples, to enable coordination with the amidic N.
With substrates such as 1 and 4 there is an enforced Cu(II)
interaction with the amidic N-lone pair that decouples its
conjugation with the adjacent CO. This is an alternative to
the usual Lewis acid M(II)---OC interaction; the present
work shows that both types can activate the amide toward
nucleophilic attack. A referee34 has offered that this mode of
binding of the Cu(II) to the amidic N activates the substrate for
the initial steps of the reaction because it renders the system
more like an acylammonium35 than a regular amide. Because
the binding of the metal ion to amides 4 and 1 is relatively
strong, the reduction of amidic resonance stabilization (as
measured by the decrease in the barrier to rotation36 or effects
on solvolytic reactivity) is brought about by utilizing the
binding energy of the Cu(II) to the two 2-picolyl groups.
However, according to the DFT computed rotational barriers
for 4b and 4b:Cu(II):(−OMe)(HOMe) as well as 1 and
1:Cu(II):(−OMe)(HOMe), there is only a 3.4 and 4.9 kcal/
mol reduction of the rotational barrier in the Cu(II)
complexes.37 This is consistent with the experimental results
for Lectka et al.36 and suggests that the Cu(II) binding to
substrate does not reduce the amidic resonance nearly as much
as would be anticipated by an acylammonium analogue.
Nevertheless, the very large acceleration of the methanolytic
reaction provides a small-molecule example supporting the
5. EXPERIMENTAL SECTION
a. Materials. Methanol (99.8%, anhydrous) and acetonitrile
(99.8%, anhydrous) were purchased from EMD Chemicals. Trifluor-
omethanesulfonic acid (HOTf, ≥99%), methanol-OD (99.5 atom %
D), 2-pyridinecarboxaldehyde (99%), 2-aminomethylpyridine (98%),
4-nitrobenzoyl chloride (98%), benzoyl chloride (99%), 4-methox-
ybenzoyl chloride (99%), 3,5-dinitrobenzoyl chloride (98+%), 4-
chlorobenzoyl chloride (99%), 4-toluoyl chloride (98%), 3-nitro-
benzoyl chloride (98%), and triethylamine (99%) were obtained from
Aldrich. Chloroform-d (99.8% D), methylene chloride-d2 (99.9% D),
and Cu(OTf)2 (98%) were obtained from TCI America Laboratory
Chemicals; 2,4,6-collidine (98%) was obtained from BDH Laboratory
Reagents.
1
b. General Methods. All H NMR spectra were determined at
400 MHz and 13C NMR spectra at 100.58 MHz. All high-resolution
mass spectra were determined by ESI-TOF. CH3OH2+ concentrations
were determined potentiometrically using a combination glass Fisher
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Scientific Accumet electrode model no. 13-620-292 calibrated with
certified standard aqueous buffers (pH 4.00 and 10.00) as described
previously.43 The sspH values in methanol were determined by
subtracting a correction constant of −2.2422 from the electrode
readings and the autoprotolysis constant for methanol was taken to be
10−16.77 M2. The sspH values for the kinetic experiments were measured
at the end of the reactions to avoid the effect of KCl leaching from the
electrode.
c. Synthesis of Materials, Dipicolylamine (N,N-bis(2-picolyl)-
amine) and 4a−g. 5.c.1. N,N-bis(2-picolyl)amine or Dipicolyl-
amine. A modification of the literature procedure was used.44 To a
solution of 2-pyridinecarboxaldehyde (4.44 mL, 46 mmol) in dry
MeOH (150 mL) was added 2-aminomethylpyridine (4.76 mL, 46
mmol) at room temperature (RT) after which the brown mixture was
stirred for 5 h. Sodium borohydride (3.5 g, 92 mmol) was added in
small portions with stirring, maintaining the reaction at 0 °C using an
ice bath. The mixture changed color from brown to yellow and was
stirred for 15 h at room temperature. Conc. HCl was added slowly to
adjust the pH to 1, and the solution was stirred for 2 h. Next, a
saturated solution of NaOH was added to adjust the pH to 11. The
reaction mixture was filtered, and the solvent was removed under
vacuum. Water was added to the residue; the aqueous mixture was
extracted twice with CH2Cl2, and the combined extracts dried over
anhydrous magnesium sulfate and filtered. The solvent was removed
under vacuum. The product was obtained as a brown oil in 85% yield
(7.78 g, 39.1 mmol).
N,N-bis(2-picolyl)benzamide.. The compound was obtained as a
brown oil in 80% yield (1.40 g, 4.02 mmol).
HRMS: calculated for C19H16N4O3 348.1222 amu, found 348.1231
amu; 1H NMR (CD2Cl2, 25 °C): δ 4.62 (s, 2H), 4.80 (s, 2H), 7.13 (d,
J = 7.48, 1H), 7.21−7.25 (q, 2H), 7.38 (d, J = 7.18 Hz, 1H), 7.57 (t,
1H), 7.66−7.72 (q, 2H), 7.96 (dt, Jd = 1.55 Hz, Jt = 7.58 Hz, 1H),
8.21−8.24 (dq, Jq = 4.80 Hz, 1H), 8.52 (t, 1H), 8.54 (d, J = 4.05 Hz,
1H), 8.62 (d, J = 3.75 Hz, 1H); 13C NMR (CD2Cl2, 25 °C): δ 50.9,
54.6, 122.4, 122.8, 122.9, 123.2, 124.6, 130.0, 133.7, 137.07, 137.13,
138.4, 148.4, 149.7, 150.3, 156.3, 157.2, 170.2; ε260 nm = 9233 193
M−1 cm−1.
5.c.5. 4-Chloro-N,N-bis(2-picolyl)benzamide (4d). This compound
was synthesized from dipicolylamine (1 g, 5.02 mmol), 4-
chlorobenzoyl chloride (1.05 g, 6.02 mmol) and triethylamine (0.84
mL, 6.02 mmol) using a procedure similar to that above for the
preparation of 4-nitro-N,N-bis(2-picolyl)benzamide. The compound
was obtained as pale yellow needles in 45% yield (0.76 g, 2.26 mmol).
HRMS: calculated for C19H16N3OCl 337.0982 amu, found
1
337.0975 amu; H NMR (CD2Cl2, 25 °C): δ 4.63 (s, 2H), 4.78 (s,
2H), 7.14 (d, J = 7.52 Hz, 1H), 7.21 (bs, 2H), 7.33 (d, J = 8.59 Hz,
3H), 7.52 (d, J = 8.59 Hz, 2H), 7.68 (bs, 2H), 8.52 (d, J = 2.50 Hz,
1H), 8.58 (d, J = 2.70 Hz, 1H); 13C NMR (CD2Cl2, 25 °C): δ 50.7,
54.8, 122.1, 122.7, 122.9, 128.9, 129.0, 135.2, 135.9, 137.0, 149.6,
150.2, 156.8, 157.5, 171.6; ε260 nm = 13490 172 M−1 cm−1; melting
point: 73 °C.
5.c.6. N,N-bis(2-picolyl)benzamide (4e).14 This was synthesized
from dipicolylamine (1.42 g, 7.13 mmol), benzoyl chloride (1.20 g,
8.56 mmol) and triethylamine (1.20 mL, 8.56 mmol) using a
procedure similar to that above for the preparation of 4-nitro- N,N-
bis(picolyl)benzamide. The crude product was purified by column
chromatography on silica gel using EtOAc/MeOH (95:5) as the
eluent. The compound was obtained as a pale yellow solid in 65% yield
(1.40 g, 4.63 mmol).
HRMS: calculated for C12H13N3 199.1109 amu, found 199.1102
amu; 1H NMR (CD2Cl2, 25 °C): δ 2.37 (bs, 1H), 3.91 (s, 4H), 7.13−
7.16 (m, 2H), 7.33 (d, J = 8.11 Hz, 2H), 7.63 (td, J1 = 7.67 Hz, J2 =
16.69 Hz, 2H), 8.51 (d, J = 4.91 Hz, 2H); 13C NMR (CD2Cl2, 25 °C):
δ 55.0, 122.3, 122.5, 136.7, 149.5, 160.3.
5.c.2. 4-Nitro-N,N-bis(2-picolyl)benzamide (4b). To a solution of
dipicolylamine (1.5 g, 7.53 mmol) in CH2Cl2 was slowly added 4-
nitrobenzoyl chloride (1.7 g, 9.16 mmol) and triethylamine (1.27 mL,
9.16 mmol). The mixture was refluxed for 3.5 h then stirred for 2 h at
room temperature. The reaction mixture was washed with water (2×),
saturated sodium carbonate solution (2×), and finally with water (2×),
then dried over anhydrous MgSO4. The CH2Cl2 was removed under
vacuum, and the crude product was purified by column chromatog-
raphy on silica gel using CH2Cl2/MeOH (90:10) as the eluent. The
solvent was removed under vacuum, and the resulting solid was
recrystallized in anhydrous ethyl ether and ethyl acetate. The product
was obtained as fine pale yellow needles in 75% yield (1.97 g, 5.65
mmol).
HRMS: calculated for C19H16N4O3 348.1222 amu, found 348.1231
amu; 1H NMR (CD2Cl2, 25 °C): δ 4.59 (s, 2H), 4.80 (s, 2H), 7.11 (d,
J = 7.80 Hz, 1H), 7.20−7.24 (q, 2H), 7.36 (d, J = 7.80 Hz, 1H), 7.64−
7.72 (m, 2H), 7.77 (d, J = 8.98 Hz, 2H), 8.19 (d, J = 8.99 Hz, 2H),
8.53 (d, J = 4.70 Hz, 1H), 8.60 (d, J = 4.70 Hz, 1H); 13C NMR
(CDCl3, 25 °C): δ 50.4, 54.1, 121.9, 122.5, 122.78, 122.82, 123.6,
128.3, 136.8, 142.3, 149.4, 150.0, 155.6, 156.5, 170.4; ε260 nm = 14940
90 M−1 cm−1; melting point: 95 °C.
5.c.3. 3,5-Dinitro-N,N-bis(2-picolyl)benzamide (4a). This com-
pound was synthesized from dipicolylamine (1 g, 5.02 mmol), 3,5-
dinitrobenzoyl chloride (1.38 g, 6.02 mmol), and triethylamine (0.84
mL, 6.02 mmol) using a procedure similar to that above for the
preparation of 4-nitro-N,N-bis(2-picolyl)benzamide. The compound
was obtained as pale yellow needles in 68% yield (1.34 g, 3.42 mmol).
HRMS: calculated for C19H15N5O5 393.1073 amu, found 393.1065
amu; 1H NMR (CD2Cl2, 25 °C): δ 4.61 (s, 2H), 4.78 (s, 2H), 7.15 (d,
J = 7.50 Hz, 1H), 7.22−7.29 (m, 2H), 7.38 (d, J = 7.79 Hz, 1H), 7.67−
7.73 (q, 2H), 8.55 (d, J = 3.90 Hz, 1H), 8.69 (d, J = 3.90 Hz, 1H),
9.02−9.04 (m, 3H); 13C NMR (CD2Cl2, 25 °C): δ 51.1, 119.8, 123.0,
123.1, 123.2, 123.6, 128.7, 137.2, 137.3, 140.3, 148.8, 149.8, 150.5,
155.5, 156.7, 168.1; ε235 nm = 20390 651 M−1 cm−1; melting point:
120 °C.
HRMS: calculated for C19H17N3O 303.1372 amu, found 303.1359
1
amu; H NMR (CD2Cl2, 25 °C): δ 4.65 (s, 2H), 4.80 (s, 2H), 7.15−
7.21 (m, 3H), 7.33−7.40 (m, 4H), 7.51−7.54 (m, 2H), 7.64−7.69 (m,
2H), 8.52 (d, J = 12.25 Hz, 2H); 13C NMR (CD2Cl2, 25 °C): δ 50.7,
54.9, 122.0, 122.6, 122.8, 127.3, 128.7, 129.9, 136.8, 137.0, 149.7,
150.2, 157.2, 157.7, 172.6; ε260 nm = 8289 137 M−1 cm−1; melting
point: 66 °C.
5.c.7. 4-Methyl-N,N-bis(2-picolyl)benzamide (4f). This compound
was synthesized from dipicolylamine (1 g, 5.02 mmol), p-toluoyl
chloride (0.93 g, 6.02 mmol), and triethylamine (0.84 mL, 6.02 mmol)
using a procedure similar to that above for the preparation of 4-nitro-
N,N-bis(2-picolyl)benzamide. The crude product was purified by
column chromatography on silica gel using EtOAc/MeOH (95:5) as
the eluent. The compound was obtained as fine white needles in 76%
yield (1.21 g, 3.82 mmol).
HRMS: calculated for C20H19N3O 317.1528 amu, found 317.1519
amu; 1H NMR (CD2Cl2, 25 °C): δ 2.34 (s, 3H), 4.67 (s, 2H), 4.79 (s,
2H), 7.16−7.21 (m, 5H), 7.37 (d, J = 6.72 Hz, 1H), 7.41 (d, J = 8.07
Hz, 2H), 7.68 (t, 2H), 8.52 (d, J = 12.88 Hz, 2H); 13C NMR (CD2Cl2,
25 °C): δ 21.5, 50.7, 54.9, 121.8, 122.5, 122.8, 127.3, 129.3, 133.7,
137.0, 140.3, 149.6, 150.1, 172.7; ε255 nm = 8911
melting point: 103 °C.
44 M−1 cm−1;
5.c.8. 4-Methoxy-N,N-bis(2-picolyl)benzamide (4g). This was
synthesized from dipicolylamine (1.52 g, 7.63 mmol), 4-methox-
ybenzoyl chloride (1.56 g, 9.15 mmol), and triethylamine (1.27 mL,
9.15 mmol) using a procedure similar to that above for the preparation
of 4-nitro-N,N-bis(picolyl)benzamide. The crude product was purified
by column chromatography on silica gel using EtOAc/MeOH (90:10)
as the eluent. The compound was obtained as fine white needles in
55% yield (1.4 g, 4.20 mmol).
HRMS: calculated for C20H19N3O2 333.1477 amu, found 333.1471
1
amu; H NMR (CD2Cl2, 25 °C): δ 3.80 (s, 3H), 4.75 (bs, 4H), 6.86
(d, J = 8.76 Hz, 2H), 7.20 (t, 3H), 7.36 (s, 1H), 7.51 (d, J = 8.77 Hz,
2H), 7.68 (td, J1 = 7.76 Hz, J2 = 17.03 Hz, 2H), 8.55 (bs, 2H); 13C
NMR (CD2Cl2, 25 °C): δ 55.7, 113.9, 122.6, 128.7, 129.3, 137.0,
161.2, 172.7; ε255 nm = 15190 620 M−1 cm−1; melting point: 83 °C.
5.c.4. 3-Nitro-N,N-bis(2-picolyl)benzamide (4c). This compound
was synthesized from dipicolylamine (1 g, 5.02 mmol), 3-nitrobenzoyl
chloride (1.12 g, 6.02 mmol), and triethylamine (0.84 mL, 6.02 mmol)
using a procedure similar to that above for the preparation of 4-nitro-
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d. General UV−vis Kinetics. The Cu(II)-catalyzed methanolyses
of the Cu(II):(−OCH3)(HOCH3) complexes of 4a−g were followed
at 360 nm for the disappearance of the 4:Cu(II):(−OCH3)(HOCH3)
complex using a UV−vis spectrophotometer with the cell compart-
ment thermostatted at 25.0 0.1 °C. The reactions were conducted in
the presence of buffers composed of various ratios of 2,4,6-collidine
and HOTf (sspH 7.2, 7.6, and 7.9) to maintain the sspH in methanol. A
typical kinetic experiment involved preparing a methanol solution
containing buffer (10−20 mM) and Cu(II) (1.0−2.0 mM) in a 1 cm
path length quartz cuvette. Initiation of the reaction involved addition
of an aliquot of the preformed 4:Cu(II) complex (0.5 mM) in
acetonitrile to the buffered methanol solution to achieve the desired
concentrations of the reaction components in a final volume of 2.5
mL. The absorbance vs time traces were fit to a standard first order
exponential equation to obtain the observed first order rate constants
(kobs). The rate constants for the methanolysis of 4:Cu(II):(−OCH3)
in the presence of excess Cu(II), required to ensure complete binding,
exhibited small buffer and Cu(II) concentration effects. The observed
kobs values were extrapolated to zero buffer concentration for each
[Cu(OTf)2] using three buffer concentrations (10 mM, 15 mM, 20
mM). These extrapolated values were then extrapolated to zero excess
complete citation for reference 25, 29 pages. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: rsbrown@chem.queensu.ca. Phone: 613-533-2400.
Fax: 613-533-6669.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the generous support of
the Natural Sciences and Engineering Research Council of
Canada (NSERC) and Queen’s University. In addition,
M.A.R.R. thanks the Government of Ontario and Queen’s
University for a QEII-GSST. R.A.A.O. also thanks the
Government of Ontario and Queen’s University for the
award of a 2012 Summer Work Experience Program (SWEP)
stipend.
Cu(II) using two or three excess Cu(II) concentrations (1.0 mM, 1.5
s
s
mM, 2.0 mM) to provide corrected rate constants for a given pH.
Averages of the three rate constants for a given substrate (kx) are
presented in Table 1.
REFERENCES
■
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e. Product Analysis. The methanolysis of 4b:Cu(II):(−OCH3)-
(HOCH3) and 4g:Cu(II):(−OCH3)(HOCH3) were conducted at
higher concentration in CH3OH (10 mM 2,4,6-collidine buffer, 4 mM
Cu(II), 3 mM 4b,g). After completion of the reaction (assessed by
UV−vis spectroscopy), the solvent was evaporated using a rotary
1
evaporator, redissolved in CDCl3, and the H NMR spectrum at 400
MHz was collected. The only observable product in each case was the
corresponding methyl benzoate. The Cu(II) complex of N,N-bis(2-
picolyl)amine was not observed by 1H NMR because of Cu(II)-
induced paramagnetic broadening.
f. Solvent Kinetic Isotope Effect (SKIE) Experiments. The
SKIE experiments for Cu(II)-assisted cleavage of 4b:Cu(II):(−OCH3)-
(HOCH3) and 4b:Cu(II):(−OCH3)(HOCH3) involved the addition
of 2,4,6-collidine buffer, Cu(II), and 4b,g:Cu(II) to UV cells
containing either CH3OH or CH3OD so that the final concentrations
of buffer, Cu(II), and substrate were 10 mM, 1.5 mM, and 0.5 mM.
s
s
Triplicate competition experiments were done, and the pH and pD
s
s
s
values were measured at the end of the reactions (4b:Cu(II); pH =
7.1 0.2, pD = 7.2 0.2; 4g:Cu(II); pH = 7.4 0.2, pD = 7.4
s
s
s
s
s
s
s
0.2).
g. Activation Parameters. Kinetic experiments with 4b:Cu(II):
(−OCH3)(HOCH3) and 4g:Cu(II):(−OCH3)(HOCH3) were con-
ducted at five different temperatures from 15.0 to 55.1 °C using a
UV−vis spectrophotometer with a thermostatted cell holder. Solution
temperatures were determined using a dummy cell adjacent to the
reaction cell into which a thermometer was inserted before and after
the reaction. First order rate constants were determined in triplicate
for 0.5 mM 4b:Cu(II):(−OCH3)(HOCH3) and 4g:Cu(II):(−OCH3)-
(HOCH3) along with 1.0 mM excess Cu(II) in the presence of 10 mM
s
s
collidine buffer, pH 7.0 0.2. Eyring plots of ln(k/T) vs 1/T shown
in the Supporting Information, Figures 1S and 2S provided the ΔH⧧
and ΔS⧧ values given in Table 2.
(9) Milovic, N. M.; Badjic, J. D.; Kostic, N. M. J. Am. Chem. Soc.
2004, 126, 696.
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ASSOCIATED CONTENT
■
S
* Supporting Information
NMR characterization of compounds 4a−d,f,g, Eyring plots for
the cleavage of 4b:Cu(II):(−OCH3)(HOCH3) and 4g:Cu(II):
(−OCH3)(HOCH3) in methanol, pseudo-first order rate
constants, extrapolated rate constants for the methanolysis of
4a−g:Cu(II):(−OCH3)(HOCH3) in the presence of multiple
concentrations of buffers and [Cu(II)] at 25 °C, DFT
optimized atomic coordinates for all structures, and the
(11) Montoya-Pelaez, P.; Gibson, G. T. T.; Neverov, A. A.; Brown, R.
S. Inorg. Chem. 2004, 42, 8624.
(12) Barrera, I. F.; Maxwell, C. I.; Neverov, A. A.; Brown, R. S. J. Org.
Chem. 2012, 77, 4156.
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(14) Niklas, N.; Heinemann, F. W.; Hampel, F.; Clark, T.; Alsfasser,
R. Inorg. Chem. 2004, 43, 4663 , and references therein.
10332
dx.doi.org/10.1021/ic301454y | Inorg. Chem. 2012, 51, 10325−10333

Inorganic Chemistry
Article
−
(15) Niklas, N.; Alsfasser, R. Dalton Trans. 2006, 3188.
second order rate constant is kMeO = 4.9 × 10−9 M−1 s−1. The rate law
for reaction of the Cu(II) complex of 4b as a function of sspH is given
(16) Brohmer, M. C.; Bannwarth, W. Eur. J. Org. Chem. 2008, 4412.
̈
4b
s
(17) Brohmer, M. C.; Mundinger, S.; Brase, S.; Bannwarth, W.
as kobs = kx4b·(ssKa/(ssKa + [H+]))12. Under conditions where Ka <
̈
̈
s
Angew. Chem. 2011, 50, 6125.
[H+], the reaction is first order in [−OCH3]. Given a sspKa of 6.512 for
formation of 4b:Cu(II):(−OCH3)(HOCH3), and an autoprotolysis
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(22) For the designation of pH in non-aqueous solvents we use the
nomenclature recommended by the 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 then measured, the term swpH is used; and if the
electrode is calibrated in the same solvent and the “pH” reading is
made, then the term sspH is used. In methanol ws pH-(−2.24) = sspH and
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8.4. sspHa refers to the negative log of the acid dissociation constant for
the process 4:Cu(II):(HOCH3) ⇌ 4:Cu(II):(−OCH3) measured in,
and referenced to, solvent methanol.
4b
constant for methanol of Kauto = 10−16.77 M2, one computes that kobs
= kx4b·(ssKa/(Kauto))[−OCH3]. The apparent second order rate
constant for the reaction of methoxide with 4b:Cu(II):(HOCH3)2 is
5.3 × 10−3 s−1·1010.27 M−1 = 108 M−1 s−1. This value is 2.0 × 1016 larger
−
than the kMeO for attack of methoxide on 4b in the absence of the
Cu(II).
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́
(34) It is a valid comment that “...... a (partial) positive charge should
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CO should be less important than in a regular amide. Compared to
a “normal” amide bond this one is ... higher in energy and,
consequently, closer in energy to the transition state for methanolysis.”
We thank the referee for the opportunity to discuss this point within
the context of destabilization of a substrate through binding to a
catalyst.
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(32) The methoxide promoted reaction of 0.15 M 4b in 0.3 M
KOCH3 shows no indication of product formation after 52.5 days.
Assuming we could detect 1 mM of the product, an upper limit for the
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