Evolution of metal complex-catalysts by dynamic templating with transition state analogs

Article abstract of DOI:10.1002/ejic.201000129

The elicitation of hydrolytic catalysts from a dynamic library of imine-zinc(II) complexes (and their precursor aldehydes and amines) via templating with pro-transition state analogs (pro-TSA) is described. pro-TSA (2-pyridyl)phosphonate 2 amplifies a ben

Full text of DOI:10.1002/ejic.201000129

FULL PAPER
DOI: 10.1002/ejic.201000129
Evolution of Metal Complex-Catalysts by Dynamic Templating with Transition
State Analogs
Masaomi Matsumoto,[a] Deven Estes,[a] and Kenneth M. Nicholas*[a]
Keywords: Catalyst evolution / Templating / Transition state analogs / Zinc catalysts / Ester hydrolysis
The elicitation of hydrolytic catalysts from a dynamic library
of imine-zinc(II) complexes (and their precursor aldehydes
and amines) via templating with pro-transition state analogs
(pro-TSA) is described. pro-TSA (2-pyridyl)phosphonate 2
amplifies a benzimidazole-derived complex at the expense
of an imidazole analogue; the amplified complex is also more
active for the hydrolysis of the pyridyl ester 1a. Employing
pro-TSA pyridyl hydrate 3 with libraries of Zn complexes of
imines having nucleophilic side chains also perturbs the li-
brary in favor of imine-Zn complexes which prove to be the
more active hydrolytic agents and catalysts. The catalytic
hydrolyses exhibit both saturation kinetics and inhibition by
the pro-TSA. This process for catalyst evolution is operation-
ally simple, amenable to high throughput screening, poten-
tially applicable to a wide variety of catalytic reactions and
thus could offer a practical alternative to catalytic antibodies
and imprinted polymers.
to the template,[9b] which, if a TSA, should be the best cata-
lyst according to Pauling–Jencks. The ability of such equili-
brating systems to amplify receptors has been amply dem-
onstrated, but catalyst production via dynamic-TSA associa-
tion is very rare and has achieved only modest activities.[10]
A disulfide cyclic trimer, amplified by cationic TSAs was
reported by Sanders and co-workers[10a] to have a twofold
rate acceleration for acetal hydrolysis (compared to back-
ground) and catalyzed a cationic Diels–Alder addition with
a kcat of 1.9ϫ10–3 s–1.[10b]
Inclusion of metal complexes into dynamic libraries[11]
has great potential for TSA-based catalyst generation given
their typical labilities, strong substrate/TSA-binding, and
diverse catalytic activities. Morrow and co-workers used dy-
namic combinatorial chemistry to select chelators for ex-
tracting zinc or cadmium into chloroform.[11e] The Lehn[11a]
and Nitschke[11d] groups have demonstrated that complex
dynamic libraries of ligands can be made to form predomi-
nately one discrete product metal complex through self-se-
lection. However, no catalytic metal complexes have been
produced from dynamic libraries of metal-ligand com-
plexes.
We envisioned the evolution of hydrolytic catalysts from
a library of metal complexes in equilibrium with imine li-
gands[11] and their precursor building blocks by templating
with pro-transition state analogs to form ternary complexes,
LM(pro-TSA) (Figure 1). Considering prior studies of
metal ion catalysis of hydrolytic reactions the coordinating
metal center would promote hydrolysis by increasing the
electrophilicity of the substrate, stabilizing the developing
tetrahedral intermediate, and/or increasing the acidity and
nucleophilicity of water.[12] With a strongly coordinating
substrate, pyridyl-CO2R, addition of M–OH to the bound
Introduction
Catalysis is essential to most useful chemical reactions,
enabling the conversion to proceed at a practical rate and
often with control of chemo-, regio- and stereoselectivity.
Rational catalyst design was stimulated by Pauling’s hy-
pothesis that enzymes accelerate reactions by complemen-
tary binding (stabilization) of the transition state and by
Jencks’ proposal that protein catalysts could be produced
that are complementary to stable transition state analogs
(TSAs).[1] These ideas were later realized in the invention of
catalytic antibodies by Schultz and Lerner.[2] More recently,
TSA-complementary synthetic catalysts have been pro-
duced via polymer imprinting.[3] Although antibody and
polymer-imprinted catalysts have been developed for a vari-
ety of reactions,[4–6] their typically modest activity,[7,8] lim-
ited catalytic functionality, expensive and complex pro-
duction technology (for antibodies), and structural hetero-
geneity (for imprinted polymers) have hampered their prac-
tical use.
Seeking a new and potentially more useful process for
catalyst evolution we turned to dynamic combinatorial
chemistry,[9] in which a substrate (or potentially a TSA) is
employed to select complementary receptors (or catalysts)
that are in equilibrium with a set of chemical building
blocks. Generally, free energy minimization favors enhanced
production (amplification) of the strongest binding species
[a] Department of Chemistry and Biochemistry, University of
Oklahoma,
Norman, OK 73019, U.S.A
Fax: +1-405-325-6111
E-mail: knicholas@ou.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201000129.
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M. Matsumoto, D. Estes, K. M. Nicholas
FULL PAPER
substrate is rate-limiting (Figure 2).[13] pro-TSAs 2[14] and and (5)Zn(solv)n was thus produced from the precursor
x+
3
[15] were thus selected to simulate the TS of metal-mediated aldehydes, PyCH2CH2NH2 and Zn(OTf)2 (1:1:1:1, 50–95%
–
hydrolysis. Here we report the first examples of the elici- CH3CN/H2O, 20 °C, 24 h), established by BH4 /HPLC
tation of metal complex catalysts by dynamic templating quench/analysis.[17,18] Addition of pro-TSA
2
(0.5–
with transition state analogs.
2.0 equiv.) to the (L)Zn(solv)nx+ library (20 °C, 24 h) caused
the quantity of benzimidazole derivative 5 to be amplified
1.4-fold (and 4 attenuated by 0.9, Figure 4). That the ampli-
fication is mediated by the formation of ternary (imine)-
Zn(pro-TSA)+ complexes was shown by Job’s plots (see SI)
and ESI-MS, which showed major species of composition
(4)Zn(2)+ (m/e = 512) and (5)Zn(2)+ (m/e-562). In addition,
a competitive 31P NMR titration (monitoring the phospho-
rus nucleus in pro-TSA 2) and Scatchard analysis[19] be-
tween preformed (4)Zn(2)+ and (5)Zn(2)+ with the weaker
binding substrate analog ethyl picolinate 1b [Equation (1)]
showed the relative affinities of anionic pro-TSA 2 vs. neu-
tral 1b to be 19 for (5)Zn(2)+ and 10 for (4)Zn(2)+. These
results demonstrate both the greater affinity of LZnx+ for
the anionic pro-TSA over the neutral substrate, which
should translate into catalytic activity, as well as the
differential binding induced by the auxiliary ligands.
Figure 1. Dynamic templating of imine-Zn complexes.
(4)Zn(2)+ + 1b h (4)Zn(1b)+ + 2
(1)
Figure 2. Metal-ion catalyzed hydrolysis of pyridyl carboxyl esters.
Results and Discussion
Zinc-promoted imine exchange was employed to produce
Figure 4. Templating of (4,5)Zn(solv)x+ with pro-TSA 2. black
filled squares: reduced 5; black filled triangles: reduced 4; amplifi-
x+
sets of equilibrating imine-Zn(solv)n complexes from al-
dehydes and amines (Figure 3).[16] A 1.0:0.9 mixture of (4)- cation factor = [Ltemplated]/[Luntemplated].
Figure 3. Reversibly formed (dynamic) imine ligands.
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Evolution of Metal Complex-Catalysts by Dynamic Templating
The correlation between pro-TSA affinity and hydrolytic cleophilic side chains, e.g. 3, and hence in nucleophilic co-
reactivity was first assessed by comparing the single-turn- catalysis.[21,22] Addition of 3 to the pair (solv)Zn(6)+ (lack-
over hydrolysis of picolinate 1a (82 m) in 30% methanol/ ing an -OH) and -(7) caused a 1.7-fold increase of 7 and a
x+
MOPS (pH 7.5, 25 °C) promoted by (4)Zn(solv)n and (5) decrease of 6 by a half (L-II, Table 1 and SI). In contrast,
x+
Zn(solv)n (0.2–0.6 m), monitored at 400 nm. The sec- addition of 3 to (solv)Zn-7,8 (LIII) caused a 2.5-fold in-
ond-order rate constants (Table 1, library I) correlate quali- crease in 8 and a 0.5-fold decrease of 7. In both cases ESI-
tatively with the templating behavior, in favor of the benz- MS spectra revealed major species of composition (L)Zn(3-
imidazole complex, 1.5-fold for pro-TSA binding and three- H2O)+, suggesting formation of hemiketal ternary com-
fold in rate. Also, pro-TSA 2 (0–10 m) was found to com- plexes (Figure 5), 11 and 12. Importantly, the activity of
petitively inhibit the (L)Zn-promoted hydrolysis of 1a ap- (6)-, (7)- and (8)Zn(solv)nx+ for 1a hydrolysis (25% meth-
proximately twofold. We interpret the ligand-dependent anol/MOPS, pH 7.5, 25 °C) varied considerably, again
binding and kinetics for the 4/5-Zn system as being derived paralleling the templating trend (Table 1), i.e. (solv)nZn-(8)
primarily from the lower basicity of the benzimidazole li- Ͼ -(7) Ͼ -(6).
gand 5 (increasing the Lewis acidity of its Zn complex),[20]
Interestingly, exposing these libraries to TSA 2 has the
which should stabilize the ternary zinc complex with an-
ionic 2 and accelerates hydrolysis through transition state
stabilization.
opposite effect; addition of pro-TSA 2 elicited a 1.3-fold
amplification of 6 and a 0.6-fold attenuation of 7 in the
pair (solv)Zn(6)+ and -(7). Addition of 2 elicited a twofold
amplification of 7 and a 0.5-fold attenuation of 8 from the
pair (solv)Zn(7)+ and (8). In both these cases, amplification
elicited by 2 does not correlate with catalytic activity. This
suggests that the structure of the pro-TSA contains infor-
mation regarding the mechanism of the catalysis. Since ca-
talysis by ligands 7 and 8 most likely go through an intra-
molecular nucleophilic attack by a hydroxy, only pro-TSA
3, which has the ability to form the hemiketal adduct, is an
accurate pro-TSA for catalysis by (solv)Zn(7)+ and (8). pro-
TSA 2, which lacks the ability to exchange nucleophilic
oxygens under our experimental conditions, is a poor pro-
TSA for nucleophilic co-catalysis by the ligand. This behav-
ior illustrates the need for careful selection of the pro-TSA
to mimic the mechanism of the desired reaction.
Table 1. pro-TSA binding, amplification, and hydrolytic rate con-
stants.
LZn(solv)n+, L = TSA AF[a] k(–1 min–1), STO[b] (MTO)[c]
Library I
4
5
2
2
0.9
1.4
30
90
Library II
6
7
3
3
0.5
2.0
170
432
Library III
7
8
3
3
0.5
2.5
432
1930
Library IV
7
3
3
3
3
0.8
2.8
0.9
0.3
432 (70)
1930 (118)
202 (64)
8
9
10
Investigating a larger library (LIV) of hydroxyimine-Zn
complexes from 7–10 (Figure 3), addition of pro-TSA 3 pro-
duced a nearly threefold amplification of 8, with attenuation
of 7, 9, and 10 (Table 1). 19F NMR Job plots and ESI-
234 (45)
[a] AF (amplification factor) = [Ltemplated/Luntemplated]. [b] Single
turnover hydrolysis rate constant for 1a. [c] Multiple turnover rate
constant for hydrolysis of 1a.
MS of (7–10)Zn(solv)+ + 3 show the presence of primarily
2+
To further illustrate catalyst elicitation by TSA-templat- LZn(3)+ and some L2Zn2(3)2 species (SI). Rate constants
ing, equilibrating ligands 7–10 were produced that could for the hydrolysis of 1a by (7)-, (8)-, (9)- and (10)Zn-
x+
participate in covalent interactions with a pro-TSA via nu- (solv)n varied almost 10-fold, paralleling the templating
Figure 5. Formation of ternary complexes between (7)Zn(solv)+ and (8)Zn(solv)+ with pro-TSA 3.
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M. Matsumoto, D. Estes, K. M. Nicholas
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results. Moreover, under catalytic conditions [2.5–10 mol-% illustrating the Pauling/Jencks hypotheses for catalyst func-
LZn(solv)n vs. 1a] the initial rate constants for (solv)Zn(7– tion and evolution. Our findings thus show that metal com-
10) correlate linearly with the templating behavior with 3 (R2 plex catalysts can be effectively elicited by dynamic templat-
x+
= 0.98, Table 1, Figure 6), again with (8)Zn(solv)n being ing with transition state analogs. The process is operation-
the best catalyst. Saturation kinetic behavior (Figure 7) and ally simple, amenable to high throughput screening, and po-
competitive inhibition by 3 was observed in the hydrolyses tentially applicable to a wide variety of catalytic reactions.
x+
catalyzed by (7)Zn(solv)n (kcat/kuncat = 51, Km = 10 m) Further, we have shown that the catalytic mechanism pro-
x+
and (8)Zn(solv)n (kcat/kuncat = 172, Km = 2 m), consis- foundly influences the correct choice of TSA structure. The
tent with reversible substrate binding. The wide range in application of this catalyst evolution process for the en-
pro-TSA affinities and catalytic activity of the Zn com- hancement of activity and selectivity for other classes of
plexes of 7–10 likely originate from a combination of the metal-catalyzed reactions is under investigation.
weaker donor character of the aromatic imines 8–10 (which
could stabilize the ternary complex with 3 and increase re-
activity) and a differing involvement of the side chain
hydroxy group in the transition state caused by geometrical
(7 vs. 8–10) and steric constraints (8 vs. 9 vs. 10).
Experimental Section
General Spectroscopic Methods: H, and 19F, and 31P spectra were
1
recorded on a Varian Mercury-300 spectrometer. Mass spectra were
acquired on a Finnigan TSQ 700 spectrometer in methanol or ace-
tonitrile solution by ESI. Spectrophotometry was carried out on a
Beckman DU 640 spectrophotometer. HPLC analysis was carried
out on a Shimadzu Class VP with ZORBAX Eclipse XDB-C18
column (4.6ϫ140 mm) at 40 °C.
Materials Preparation: The following were prepared by literature
methods: p-nitrophenyl picolinate (1a),[23] phenyl (2-pyridyl)phos-
phonate (2),[24] 2-pyridyl trifluoromethyl ketone hydrate (3),[25] 2-
formyl-1-methylbenzimidazole[26] and (R,S)-1-(2-aminophenyl)eth-
anol and (R,S)-(2-aminophenyl)(phenyl)methanol.[27]
Amplification/Analysis Method. General Procedure: A 100 m stock
solution of each building block was produced by dissolving
0.1 mmol of building block in 1 mL of CH3CN. A 100 m stock
solution of Zn(OTf)2 was prepared in CH3CN. A 100 m stock
solution of TSA 2 was prepared in 1 mL of CH3CN and the free
base was produced by addition of 14 µL triethylamine. A 100 m
stock solution of TSA 3 was prepared in CH3CN. Libraries were
prepared by pipetting 50 µL aliquots of each building block and
Zn(OTf)2 into vials and diluting to 1 mL with CH3CN. Control
libraries contained no TSA, whereas templated libraries were
treated with 50–250 µL TSA stock solution 2 or 3. In cases where
the overall solvent composition was to be 50% CH3CN in water,
the samples were diluted to 0.5 mL with CH3CN and treated with
0.5 mL of water. After equilibrating 24–48 h at 20 °C, the samples
were treated with 25 mg of NaBH4 and stirred overnight with a
needle in the vial lid to vent excess pressure. Samples were then
treated with 100 µL of TFA to acidify, and diluted to 2 mL with
water. A 100 µL aliquot of each sample was then taken and diluted
to 1 mL in water to provide the HPLC sample.
Figure 6. Plot of multiple turnover rate constants vs. amplification
factor for pro-TSA 3 with Zn-7, Zn-8, Zn-9, and Zn-10.
HPLC Methods: HPLC grade acetonitrile and water with 0.1%
v/v TFA were used. Library I, II, and III: 3% acetonitrile 5 min,
gradient to 10% acetonitrile over 5 min, 10% acetonitrile 20 min.
Library IV: method 1: 5% acetonitrile, gradient to 10% acetonitrile
over 5 min, 10% acetonitrile, 20 min. method 2: 15% acetonitrile,
30 min. Library deconvolution was carried out by preparing librar-
ies that were missing one of the building blocks. In cases where
there were only three building blocks and two possible Schiff bases,
peaks were identified by injecting samples containing building
blocks and comparing to chromatograms of libraries containing
only one of the possible reduced Schiff bases.
Figure 7. Dependence of the hydrolytic rate constant on the con-
centration of substrate (4-nitrophenylpicolinate) (1a) by the catalyst
7-Zn(solv).
Conclusions
A set of aldehyde and amine building blocks have been
employed to generate equilibrating ZnII-imine complex li-
braries which respond to templating with pro-transition
state analogs. The complexes which are thus amplified have
Job’s Plot Analysis of Binding Stoichiometry: A 100 m stock solu-
tion of Schiff base-zinc complex was formed in 1 mL of CD3CN.
A 100 m stock solution of TSA 2 or 3 was prepared in 1 mL of
proven to be the most active for promoting ester hydrolysis, CD3CN, with 14 µL TEA added in the case of 3. NMR job plot
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Evolution of Metal Complex-Catalysts by Dynamic Templating
samples were prepared by combining zinc complex and TSA stock
solutions in the proportions 10 µL/ 90 µL, 25 µL/75 µL, 50 µL/
tion consisting of 700 µL of 100 m pH 7.5 MOPS buffer, 100 µL
of 1a solution, and Zn(ligand) in methanol varying from 0 to
50 µL, 75 µL/25 µL, and 90 µL/10 µL with 900 µL CD3CN. Sam- 200 µL with the remaining volume compensated by methanol. The
1
ples were analyzed by 1H-NMR and 31P NMR, and F-NMR in
the case of TSA 3.
rate of 4-nitrophenyl picolinate hydrolysis by the Schiff base-zinc
complexes was measured by spectrophotometric assay at 400 nm.
The assay was carried out at 25 °C in the presence of 75% aqueous
100 m MOPS buffer held at pH 7.5, with catalyst in excess of
substrate (single-turnover conditions) over a period of 8 min with
one reading per 14 seconds. Plotting (catalyst concentra-
tion)ϫ(substrate concentration) vs. the initial hydrolysis rate gives
the second-order rate constant. Plots of k(obs) vs. Zn complex con-
centration are provided in the SI.
A Job plot for the ternary complex of 5, zinc(II), and phenyl (2-
pyridyl)phosphonate was constructed by observing the 31P NMR
chemical shift while simultaneously varying the concentration of
Schiff base-zinc complex and phenyl (2-pyridyl)phosphonate. The
Job plot shows a local minimum at 1:1 but also a large peak in the
high phenyl (2-pyridyl)phosphonate to zinc ratio region, indicating
the formation of complexes including multiple phosphonate li-
gands.
Inhibition of 1a hydrolysis by 2 was studied under the same condi-
tions as above while holding catalyst concentration at 0.4 m and
substrate at 82 µ. The concentration of 2 was varied from 0 to
10 m. 2 appears to inhibit hydroysis by Zn(4) and Zn(5) with a
concentration dependence that levels off rapidly.
Job plots for the ternary complexes of amino alcohol Schiff bases
7, 8, 9, and 10, zinc and 3 were constructed by observing 19F NMR
chemical shift while varying Schiff base complex and 3. It was
found that the stoichiometry was dependent on the Schiff base.
Zinc complexes of 7 and 10 were found to form 2:1 complexes
with TSA 3, of the composition Zn2723 and Zn21023, whereas zinc
complexes of 8 and 9 formed the 1:1 complexes with TSA 3.
Multiple-Turnover Kinetics for the Hydrolysis of 1a Catalyzed by
Zn-imine Complexes: The hydrolysis of 1 was carried out under
multiple turnover conditions (excess substrate), varying the catalyst
concentration. The concentration of 1 was 0.82 m, and the cata-
lyst concentration was varied from 0.02 m to 0.08 m. Reactions
were observed for 16 min, with the region from 4–8 min used for
the analysis. The assay was carried out at 25 °C in the presence of
75% aqueous 100 m MOPS buffer held at pH 7.5, and observed
at 400 nm. The second-order rate constants for the hydrolysis of
4-nitrophenyl picolinate under multiple-turnover conditions were
70 –1 min–1, 117 –1 min–1, 63 –1 min–1, 45 –1 min–1, for Zn-7,
Zn-8, and Zn-9, and Zn-10 respectively. Plots of k(obs) vs. [Zn-
catalyst][substrate] are provided in the SI.
Job plots are provided in the SI.
ESI-MS of Ternary Complexes: ESI-MS of library mixtures for Li-
brary I under templating conditions showed the formation of ter-
nary complexes composed of zinc, Schiff base 5, and phenyl (2-
pyridyl)phosphonate, as well as ternary complexes composed of
zinc, Schiff base 4, and phenyl (2-pyridyl)phosphonate.
ESI-MS of the library II mixture shows evidence of the TSA–
Schiff base-zinc adduct. Species of interest include a zinc complex
of the adduct of 7 and 3, Zn(7)(3)(H2O) (m/z = 567.07) and a dizinc
complex of the composition Zn2(7)2(3)(H2O)2+ (m/z = 379.56).
Saturation Kinetics for Hydrolysis of 1a by Zn(7) and Zn(8): When
the 4-nitrophenyl picolinate hydrolysis assay was carried out under
conditions of excess substrate (steady state conditions), varying the
substrate concentration while holding Zn-Schiff base complex con-
centration constant, saturation behavior was observed. Kinetics
runs for zinc amino alcohol imine ligand complexes were made in
a 1-cm quartz cuvette containing 1 mL of solution consisting of
750 µL of 100 m pH 7.5 MOPS buffer, 250 µL methanol, 40 µ
Zn(7) or Zn(8), and 1a varying from 0.3 m to 1.6 m. Spectro-
photometric measurements were made at 400 nm at 25 °C over a
period of 8 min with 1 reading per 14 seconds. Vmax was 5.8ϫ10–6
Mmin–1 and 2.0ϫ10–5  min–1 for Zn-8 and Zn-7, respectively. KM
was 2.0ϫ10–3  and 1.0ϫ10–2  for Zn-8 and Zn-7, respectively.
kcat was 0.5 min–1 and 0.15 min–1 for Zn-8 and Zn-7, respectively.
Double reciprocal plots are provided in the SI.
ESI-MS analysis of the templated library mixture from Library III
(Schiff bases 7 and 8) shows a variety of zinc complexes that incor-
porate the transition state analog 3. These include TSA–
Schiff base-monozinc complexes Zn(8)(3)(H2O) (m/z = 453.05),
Zn(7)(3)(H2O) (m/z = 567.07), and dizinc complexes of the compo-
sition Zn2(8)2(3)(H2O)2+ (m/z = 365.54), Zn2(7)(8)(3)(H2O)2+ (m/z
= 373.56), Zn2(7)2(3)(-H2O)2+ (m/z = 379.56). Also present are
peaks corresponding to dizinc complexes without TSA, including
2+
Zn282 (m/z = 278.06), Zn2(8)(7)2+ (m/z = 285.04), and Zn(7)(2)2+
(m/z = 292.05).
ESI-mass spectra for these libraries are provided in the SI.
Scatchard Analysis of 4/5 Binding by NMR Titration: A 100 m
solution of Zn (4) or Zn (5) in CD3CN was prepared. A 100 m
solution of 2 in CD3CN was prepared, and 14 µL of triethylamine
was added. A 10 m solution of Zn(4)(2) or Zn(5)(2) was prepared
from these stock solutions in CD3CN. Trimethyl phosphate was
added as a 31P standard. A 1  solution of ethyl picolinate in
CD3CN was prepared. Ethyl picolinate 1b was titrated into the
10 m solution of Zn(4)(2) or Zn(5)(2) in 25 µL aliquots while ob-
serving the 31P chemical shift of TSA 2. A Scatchard treatment of
the data gives KTSA/KSA values of 10 for Zn(4) and 19 for Zn(5)(2).
The Scatchard graph is provided in the SI.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures and data for amplification
and kinetics runs, Job’s plots, MS data.
Acknowledgments
We thank Prof. Richard Taylor and Prof. Paul Cook for helpful
discussions; and Prof. Cook is also thanked for allowing to use his
spectrophotometers. M. M. was partially supported by a Graduate
Assistantship in Areas of National Need (GAANN) fellowship and
D. E. by a D. van der Helm fellowship. We are also grateful for
partial support provided by the National Science Foundation
(NSF) (CHE-0911158).
Single-Turnover Kinetics for the Hydrolysis of 1a Catalyzed by Zn-
imine Complexes: Generally, a 4 m solution of each Zn(ligand)
complex was prepared in methanol (25 mL) by combining zinc
triflate, aldehyde and amine and allowing the solution to equili-
brate 48 h. Analysis by 1H NMR and borohydride reduction/HPLC
showed full conversion to the Schiff base. A 0.82 m solution of
1a was prepared in 25 mL of CH3CN. Kinetics runs for Zn(4) and
Zn(5) were made in a 1-cm quartz cuvette containing 1 mL of solu-
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Received: February 5, 2010
Published Online: March 13, 2010
1852
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