Selection of chiral zinc catalysts for the kinetic resolution of esters via dynamic templating

Article abstract of DOI:10.1021/co3001023

Dynamic combinatorial libraries of chiral tetradentate bis-imine zinc(II) complexes have been prepared and screened for (1) their discrimination of enantiomeric picolinate esters and pyridyl phosphonate transition state analogs (TSAs) and (2) their cataly

Full text of DOI:10.1021/co3001023

Research Article
pubs.acs.org/acscombsci
Selection of Chiral Zinc Catalysts for the Kinetic Resolution of Esters
via Dynamic Templating
R. Kannappan and K. M. Nicholas*
Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman,
Oklahoma 73019, United States
S
* Supporting Information
ABSTRACT: Dynamic combinatorial libraries of chiral
tetradentate bis-imine zinc(II) complexes have been prepared
and screened for (1) their discrimination of enantiomeric
picolinate esters and pyridyl phosphonate transition state
analogs (TSAs) and (2) their catalytic activity and selectivity
for enantioselective methanolysis of racemic picolinate esters.
The zinc complexes are in equilibrium with their imine ligands
as well as with the aldehyde and amine building blocks that
form them, enabling the composition of the library to adapt in response to the introduction of coordinating substrates or TSAs.
Binary (L)Zn(OTf)(solv)+ complexes are generated either individually or in libraries from chiral tartrate-derived diamines (2,3)
and a set of N-heterocyclic aldehydes (4−12) and the distribution of complexes established by ESI-MS analysis. Binding studies
of the (diimine)Zn(OTf)2 complex libraries with enantiomeric R- and S-2-pyridyl phosphonate TSA 13 show chiral
discrimination via formation of diastereomeric LZn(R/S-13)+ complexes with low to moderate enatioselectivity ratios, kR/kS (α),
ranging from 0.5 to 5.0; corresponding templating of selected binary complexes with the enantiomeric substrates,
PyrCO2CH(OH)Ph (1), show negligible chiral recognition. The rate constants for methanolysis of the R- and S-esters,
PyrCO2CH(OH)Ph (1) catalyzed by several L*Zn(OTf)2 complexes range in value several fold depending on L and with
enantioselectivity ratios, kR/kS (α), ranging from 0.76 to 2.8.
KEYWORDS: chiral zinc catalysts, esterolysis, dynamic templating, transition state analogs, ESI-MS screening
set of imine-metal complexes, in equilibrium with their
constituent aldehydes and amines, with TSAs.8 A good
correlation between ternary (imine)Zn(TSA) complex for-
mation and the hydrolytic activity of the (imine)ZnX2
complexes was found as predicted by the Pauling−Jenks
model for enzyme and antibody catalysis.9
INTRODUCTION
■
In biological systems metalloprotease and -esterase enzymes
catalyze the hydrolysis of amides and esters with remarkable
efficiency by making use of the protein-ligated metal center to
electrophilically activate the substrate and, in some cases, to
increase the acidity and the nucleophilicity of coordinated
water.1 For example, carboxypeptidase A and thermolysin are
Zn(II)-enzymes that catalyze the hydrolysis of peptides and O-
acyl derivatives of α-hydroxycarboxylic acids.2,3 To better
understand the factors that control the detailed properties of
the active sites of zinc enzymes, numerous model complexes
have been investigated.4 Studies of scorpionate- and other
tripodal-Zn complexes have led to the elucidation of key
mechanistic features of the catalysis by Zn-enzymes.5 These
include biomimetic hydrolyses as well as the modeling of
intermediates of peptidase and carbonic anhydrase catalytic
cycles.6 The hydrolysis and alcoholysis of esters, often
possessing coordinating cofunctionality, can be catalyzed by
divalent metal ions such as Co2+, Ni2+, Zn2+, and Cu2+ with kcat/
kuncat values as large as 108.7
To apply this approach to high throughput combinatorial
catalyst discovery, an efficient analytical method is needed to
identify the binary and ternary metal-complexes present in large
collections and to quantify the changes in composition resulting
from challenging the system with potential substrates and
TSAs. In our initial studies we employed reductive quenching
of the imine-Zn complexes to the corresponding stable amine
ligands that were analyzed and quantified by HPLC.8 Although
effective for small libraries, complete identification and
quantification of large libraries of complexes would require
extensive and customized separations for each library mixture
and quantification would be laborious for lack of a universal
detection method. ESI-MS has been found to be a good
method for determining the composition and relative amounts
of the species present in a solution under certain
conditions.17−21 This tool has been applied successfully to
We have sought to develop a new method for catalyst
selection based on the expected correlation between the
binding affinity of transition state analogs (TSAs) to a catalyst
center and the catalyst’s activity and selectivity (Figure 1). A
proof-of-concept demonstration of this principle was recently
reported for the selection of hydrolytic catalysts by templating a
Received: August 30, 2012
Revised: December 10, 2012
Published: December 16, 2012
© 2012 American Chemical Society
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Figure 1. Relationship between binding of TSAs and catalytic activity/selectivity.
Figure 2. LZnX2-catalyzed methanolysis of chiral picolinate ester.
Figure 3. Building block amines and aldehydes for binary LZn(OTf)2 complexes (A).
the characterization of various polynuclear metal complexes22,23
and other noncovalent ligand-macromolecular associates, for
example, ligand-DNA and ligand-protein complexes present in
equilibrium.12,24−26 In the present report we demonstrate the
efficacy of ESI-MS as a tool for the identification and
semiquantification of the composition of libraries of equilibrat-
ing LZnX+, LZnX(Sub)+, and LZn(TSA)+ complexes.
Many valuable applications of catalysis derive from the
catalyst’s ability to control product selectivity. Stereoselective
hydrolytic reactions, including kinetic resolutions, are partic-
ularly valuable synthetically.10 Enzymatic enantioselective
hydrolysis, alcoholysis, and transesterification reactions have
achieved good efficiencies and are applied in the industrial
production of optically active compounds, but their substrate
scope is often limited. In contrast, the development of
enantioselective solvolytic reactions using synthetic metal
complex catalysts has been quite limited, the most notable
success being achieved for the kinetic resolution of alkenyl
esters, ethers, and azalactones,11 of epoxides by PdCl2(MeCN)2
and Cu(OAc)2-SEGPHOS,12 and of amino acid esters by
lanthanide-Schiff base complexes.13 To date few systems have
achieved good enantioselectivities, and the substrate scope has
been quite limited. Hence, there is clearly a need for new
classes of synthetic catalysts and reactions for kinetic resolution.
Seeking applications of the dynamic TSA-templating
approach to catalyst selection we have targeted the kinetic
resolution of chiral, racemic alcohols via their picolinate esters,
employing homochiral imine-metal complex catalysts and
suitable TSAs (Figure 2). The facile hydrolysis of coordinating
picolinate esters has found use in organic synthesis, as a
protecting group for alcohols (deprotected by MeOH/
Zn(OAc)2)14 and in the Mitsunobu stereoinversion of alcohols
(the picolinate removed by MeOH/Cu(OAc)2).15 In our initial
investigation a series of bi/tridentate chiral Zn-(imine)
complexes was prepared from mono-N-sulfonyl derivatives of
(1R,2R)-diaminocyclohexane, N-heterocyclic aldehydes, and
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Figure 4. Generation of binary LZn(OTf)+ (A) complexes.
Table 1. Binary Complexes, LZn(OTf)+ Detected by ESI-MS
(CH3OH)
zinc salts. The methanolysis rate of the chiral picolinate ester 1
catalyzed by these Zn-Schiff base complexes was found to vary
approximately a hundred-fold and in a complex way depending
on the imine ligand and the Zn-counteranion, kobs = 5.0 ×
10−6−4.8 × 10−4 M−1sec−1.16 However, selected L*ZnX2
complexes showed little difference ( 10%) in their catalytic
rates for hydrolysis of enantiomeric substrates, that is,
enantioselectivities.
From our initial study we recognized the need both for an
effective method to analyze the composition of larger libraries
of metal complexes for high throughput screening and for
improved chiral recognition/induction among the complexes.
To improve enantioselectivity we sought tight-binding, higher
denticity (4 vs 3) chiral polydentate ligands that would impose
a more well-defined, chiral environment for the Zn-center in its
coordination to chiral substrates and TSAs.
m/z
(found)
a
library
binary complexes
b
Library 1 : diamine 2 +
aldehydes 4,8,10 +
Zn(OTf)2
[(2−4−10)64Zn(OH)(H2O)]+
440.1
[(2−10−10)64Zn(OH)(H2O)]+
[(2−4−4)64Zn(OTf)]+
437.1
557.1
592.1
595.1
747.2
[(2−8−10)64Zn(OH)(H2O)]+
[(2−4−8)64Zn(OH)(H2O)]+
[(2−8−8)64Zn(OH)(H2O)]+
b
Library 2 : diamine 2 +
[(2−5−11)64Zn(OCH3)(H2O)]+
498.2
aldehydes 5, 6, 7, 9, 11
+ Zn(OTf)2
[(2−6−11)64Zn(OCH3)(H2O)]+
[(2−5−5)64Zn(OCH3)(H2O)]+
[(2−9−11)64Zn(OCH3)(H2O)]+
[(2−9−9)64Zn(OCH3)(H2O)]+
[(2−7−7)64Zn(OCH3)(H2O)]+
510.2
513.2
518.2
557.2
609.2
RESULTS AND DISCUSSION
■
In considering new ligand types we selected C2-chiral diamines
2 and 3 based on computational molecular models which
indicated that the tetradentate Schiff base (diimine) complexes
formed by condensation of these diamines with heterocyclic
aldehydes would enforce a (nonplanar) tetrapodal geometry,
leaving two cis-coordination sites to bind either a bidentate
substrate or a monodentate substrate and an alkoxide or
hydroxide nucleophile (Figure 3). Diamine ligands of this type
were originally developed by Seebach et al.27 Metal (Co, Cu,
and Rh) complexes derived from these chiral diimines were
recently prepared by Nindakova et al.,28 and these complexes
have seen a few applications in asymmetric metal-catalyzed
reactions, including nitroaldol, transfer hydrogenation, and
borohydride reduction of ketones29 with variable enantiose-
lectivities.30
c
Library 3 : diamine 3 +
[(3−4−5)64Zn(OTf)]+
889.2
aldehydes 4, 5, 6, 7, 8, 9
+ Zn(OTf)2
[(3−4−9)64Zn(OTf)]+
[(3−5−5)64Zn(OTf)]+
[(3−5−9)64Zn(OTf)]+
[(3−9−9)64Zn(OTf)]+
[(3−7−9)64Zn(OTf)]+
[(3−7−7)64Zn(OTf)]+
[(3−5−8)64Zn(OTf)]+
[(3−8−9)64Zn(OTf)]+
[(3−7−8)64Zn(OTf)]+
911.2
917.2
939.2
961.2
987.3
1013.2
1041.3
1063.3
1089.2
a
b
m/z corresponding to 64Zn (48.6% isotopic abundance). Library 1
c
1. Generation and Analysis of Binary LZn(OTf)2
Complexes. The approach to and attainment of equilibrium
at room temperature among sets (libraries) of the binary
LZn(OTf)2 complexes A could be monitored by ESI-MS. The
complexes were generated in MeOH by combining one or
more aldehyde(s) (each 2 equiv) with the diamine (1 equiv)
and ZnOTf2 (1 equiv) at room temperature (rt) (Figure 4).
Sampling and analysis by ESI-MS over several hours revealed
the formation of various [LZn(OTf)]+ species as well as
[LZn(OCH3)H2O]+ and [LZn(H2O)OH]+ (Table 1; note
H2O is produced from aldehyde/amine condensation to the
diimine L). Zinc-containing ions are easily recognized by their
distinctive isotope pattern (64Zn 48.6%, 66Zn 27.9%, 68Zn
18.8%). A constant composition and relative intensity (ion
abundance) of ions compared to the added noninteracting salt,
and 2 is produced in MeOH. Library 3 is produced in CH3CN.
detected, albeit with different ion counts. In library 2, however,
only 6 of 14 possible binary complexes were detected with
appreciable ion intensities, and in library 3 (derived from
diamine 3) only 9 of 21 possible complexes were detected.
Although the ion abundances among the [LZn(OTf)]+
complexes with different L may not be quantitatively correlated
with their relative amounts because of their varying sizes, ligand
variations and solvation, these observations indicate that the
distribution of complexes in the libraries at equilibrium (and
hence their relative stabilities) varies substantially. Both steric
and electronic effects apparently influence the composition of
the libraries as illustrated by the absence of complexes in
libraries 2 and 3 derived from bulky aldehyde 6 and the
differences in abundance among the complexes derived from
the heterocyclic aldehydes of different basicities (imidazole,
pyridine, quinoline). MS analysis of the binary (and
subsequently ternary) complex libraries thus facilitates the
−
Bu4N+PF6 , was reached within 24 h, indicative of equilibrium
being reached. It is noteworthy that Zn-containing species
lacking coordinated L were not detected, indicating a large Kf
for LZnX+.31 In library 1 all six possible binary complexes were
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Figure 5. Formation of ternary LZn(TSA)+ complexes.
identification of the most energetically favored species and the
selection of promising candidates for synthesis and individual
catalytic screening, minimizing time spent on less promising
candidates.
8)Zn(13)]+ (library 4, Table 2). A constant composition and
relative intensity of ions is reached within approximately five
Table 2. ESI-MS of Ternary Complexes [LZn(R/S-TSA
2. Generation and Analysis of Ternary LZn(TSA)+
Complexes. Phosphonate esters have been employed as
carboxyl ester hydrolytic TSAs, mimicking the putative
hydrolytic pseudotetrahedral transition state geometry.32 For
the Pyr-CO2R substrates of this study corresponding
phosphonate derivatives, R- and S-Pyr-PO(OH)CHMePh
(13) were selected and prepared from their respective
enantiomeric benzylic alcohols (Figure 5).33 These compounds
were expected to bind to the (diimine)Znn+ species in an N,O-
bidentate mode mimicking the transition state and intermediate
from hydroxide/alkoxide attack on the Zn-activated pyridine
ester.7a,33,34
a
(13)]+
ternary
complexes
m/z
(found)
library
Library 4: diamine 2 + aldehyde 4,8,10 +
Zn(OTf)2 + R- or S-13
[(2−4−
667.2
819.2
917.3
726.3
740.3
748.2
754.3
762.3
774.3
788.3
796.2
822.3
10)64Zn(13)]+
[(2−8−10)64Zn
(13)]+
[(2−8−8)64Zn
(13)]+
Library 5: diamine 2 + aldehyde 5,6,7,9,11 +
Zn(OTf)2 + R- or S-13
[(2−5−5)64Zn
(13)]+
[(2−5−6)64Zn
(13)]+
Binding of the (diimine)Zn(OTf)+ to the pyridyl phospho-
nate TSA 13 and the composition of the resulting ternary
LZn(13)+ complexes was established by the Job plot
[(2−5−9)64Zn
(13)]+
[(2−6−6)64Zn
(13)+
(continuous variation) method8,16 and by ESI-MS. Thus, H
1
[(2−6−9)64Zn
(13)]+
NMR monitoring of the chemical shift (δ) of the imine proton
signal (CHN-) of the LZn-species derived from diamine 2
and imidazole aldehyde 6 as a function of the LZn/TSA(13)
ratio provided a plot with a single maximum at LZn/13 = 1
(Figure 6), supporting the formation of a ternary complex of
composition [LZn(13)]+.
[(2−5−7)64Zn
(13)]+
[(2−6−7)64Zn
(13)]+
[(2−7−9)64Zn
(13)]+
[(2−7−7)64Zn
(13)]+
a
Amine 2 (0.05 mM), aldehyde (0.10 mM), zinc triflate (0.05 mM),
and Bu4NPF6 (0.05 mM, internal standard) are mixed in methanol
overnight (rt).
minutes when normalized to the concentration of non-
−
coordinating salt Bu4N+PF6 added as an internal reference
(Figure 7).
Similarly, treatment of library 2 (from 2, aldehydes- 5, 6, 7, 9,
11 + Zn(OTf)2) with R- or S-13 revealed the formation of
ternary complexes LZn(13)+ by ESI-MS (library 5, Table 2).
Among 15 possibilities, we detected a common set of 9
LZn(TSA-13)+ complexes with either enantiomer of 13. A
summary of the ternary complexes detected is given in Table 2.
Although the ion abundances among LZn(TSA)+ with
different auxiliary Ls may not be quantitatively correlated
with concentration, one can expect that the ion detection
response for pairs of diastereomeric LZn(TSA)+ complexes that
have the same ligand L and enantiomeric TSAs should be very
similar.35 Hence, with the inclusion of an inert reference
compound, parallel reactions of the LZn(OTf)2 libraries with
the R- and S-TSAs 13 with ESI-MS-analysis were conducted to
Figure 6. Job plot for the complexation (2−6−6)Zn(OTf)+ with S-
TSA (13) at a total concentration of 10 mM in CD3OD; weighted
value of imine proton NMR chemical shift δ × complex concentration
[mM] (x-axis) as a function of [cat]0/[cat]0+[S-TSA]0 (y-axis).
ESI-MS analysis of solutions of both individual and sets of
(diimine)Zn(OTf)2 complexes after treatment with R- or S-
TSA 13 also showed the formation of ternary LZn(TSA-13)+
complexes. Treatment of binary complex library 1, derived from
diamine 2, aldehydes (4,8,10), Zn(OTf)2 with TSA-13 under
equilibrating conditions showed the formation of three (out of
6 possible) LZn(13)+ ternary complexes for each enantiomer of
13: [(2−4−10)Zn(13)]+, [(2−8−10)Zn(13)]+, and [(2−8−
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Figure 7. Time-dependent ESI−MS monitoring of ternary complexes
from library 1 + R-TSA (13) = library 4; TC = ion count of complex,
Figure 9. Amplification of LZn(13)+ from (2-5, -6, -7, -9,
-11)Zn(OTf)2 + R- or S-13 analyzed by ESI-MS at 24 h. The
calculated relative abundance = (ion count of peak/ion count of
internal standard)/sum over all ions of (ion count of peak/ion count
of internal standard).
−
IS = ion count of internal standard, Bu4N+ PF6 .
determine the relative binding affinities, that is, the stereo-
discrimination (selectivity) factor, α, of the various LZn(OTf)+
complexes toward the enantiomeric TSAs. Figure 8 shows a
section of the ESI-mass spectra for the ternary complexes
produced from the enantiomeric TSAs 13 and the LZn
complexes of library 2 = library 4. An amplification graph
(Figure 9) is produced by plotting the (2-n-n)Zn(R- or S-13)
ligands derived from 3. The convenient and rapid ESI-MS
analysis of the combinatorial libraries of binary LZn(OTf)-
complexes from diamine 2 with the enantiomeric TSAs, R- and
S-13, facilitates the identification and selection of candidate
catalysts for testing, avoiding the more labor intensive, one-at-a-
time preparation and separate testing of all possible candidates.
3. Formation of LZn(Sub)+. The rate acceleration induced
by a catalyst is considered to be the result of differential binding
stabilization of the substrate relative to the transition state, as
reflected in the activation energy. It was of interest, therefore, to
assess the binding affinity and here, especially the enantio-
differentiation of the chiral substrate, S-ester, by the chiral LZn
complexes (Figure 10). Complexation of ester S-1 by the
polyimine complexes Zn(2−6−6)(OTf)2 and Zn(2−9−9)-
(OTf)2 was suggested by NMR spectroscopy, which shows a
continuous shifting of the imine N−H signal as a function of
the added substrate 1 (in acetonitrile). The resulting Job plot
(see Supporting Information) showed maxima at both 1:1 and
approximately 9:1 Sub/Zn ratios, suggesting the formation of
ternary complexes LZn(1)12+ and, probably, LZn(1)22+. Parallel
ESI-MS experiments with Zn(2−6−6)(OTf)2 and R- or S-ester
signal intensity divided by the intensity of the Bu4N+PF6
−
internal standard (% TC/IS; TC = total ion current; IS = ion
current of internal standard) versus m/z of LZn(13)+. From
this graph one can see small R-binding preferences (≤2:1) are
found for L = 2−5−5, 2−5−9, 2−6−9, and 2−6−7; a larger
(>2:1) R-selectivity is seen with 2−5−7 and 2−7−9. Binding
of the S-TSA is preferred moderately (ca. 2:1) for complex with
L = 2−5−6, and the most S-selective complex (ca. 5:1) was
found for L = 2−6−6. This latter selectivity corresponds to
approximately a 1.0 kcal difference at equilibrium in favor of the
(2−6−6)Zn(S-13)+ complex. We could not detect ternary
complex formation in library mixtures derived from the
tetraphenyldiamine 3 with TSA 13 by ESI-MS because of the
formation of precipitates that were poorly soluble in all solvents
tested. We suspect that these intractable materials are either
36
Zn(TSA)2 or possibly polynuclear [Zn(L)(TSA)]n which
could result from weaker binding of the sterically hindered
Figure 8. Portion of ESI-MS of (a) (2-5, -6, -7, -9, -11)Zn(OTf)2 + R-13; and (b) (2-5, -6, -7, -9, -11)Zn(OTf)2 + S-13; at 24 h in MeOH.
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Figure 10. Formation of ternary LZn(substrate)+ complexes.
Figure 11. Preparation of isolable binary LZn(OTf)+ complexes.
1 in acetonitrile (1:1) also revealed the formation of (2−6−6)-
Zn(1)2+ (m/z = 360) upon addition of 1 equiv of 1 (Figure
10). Comparison of the ion intensities of the diastereomeric
ternary complexes relative to the internal standard indicated
complex libraries 1−3 and similarly found to form ternary
LZn(TSA-13)+ complexes in libraries 4,5. The catalytic activity
and enantioselectivity of the LZn(OTf)2 complexes A were
assessed by determining the initial rates (up to 15%
conversion) of methanolysis of the R- and S- 1-phenylethyl
picolinate (PEP, 1) in the presence of 0.1−1.0 mol % catalyst at
T = 292 K by 1H NMR monitoring (Figure 12). The decline of
almost equal concentrations,
10%, and thus little stereo-
differentiation of the enantiomeric substrate esters by (2−6−
6)Zn(OTf)2, which contrasts with that observed with the
corresponding complexes of the TSA 13 (Figure 7). This
indicates a greater chiral discrimination of the phosphonate
TSA relative to the substrate ester for these chiral Zn-
complexes and supports the idea that the primary determinants
of enantioselectivity are steric and electronic interactions in the
reaction’s transition state.
Figure 12. LZn(OTf)2-catalyzed methanolysis of ester 1.
4. Isolation-Characterization of Binary LZn(OTf)2
Complexes. To authenticate the LZn-complexes revealed by
ESI-MS in the combinatorial libraries 1−3 and to provide
samples for catalytic testing, we prepared and characterized
several complexes with symmetrical diimine ligands (i.e.,
derived from two identical aldehydes). These were prepared
by combining either of the chiral diamines 2 or 3 with the N-
heterocyclic aldehydes (4−12) and Zn(OTf)2 in acetonitrile at
the ester methyl doublet and a corresponding growth of the
product alcohol methyl doublet (Figure 13) were integrated to
provide concentration vs time plots that lead to the initial rates
(Figure 14) and second order rate constants listed in Table 3.
Three independent methanolysis runs on 1 catalyzed by [2−5−
5]Zn(OTf)2 showed good agreement ( 5%) among their rate
constants, 2.0 × 10−6 M−1s−1.
1
reflux (Figure 11). Their H NMR spectra exhibited character-
istic imine NCH resonances at δ 8.2−9.2 ppm. ESI-mass
spectra (CH3CN) indicated the presence of [LZn(OTf)]+OTf−
and [LZn(OTf)(H2O)]+OTf− as major species with the
characteristic isotope pattern for Zn-containing ions (64Zn
48.6%, 66Zn 27.9%, 68Zn 18.8%). Elemental composition was
confirmed by high resolution ESI-MS showing the coordination
of LZn(OH)/MeOH and H2O (Table 1). The IR spectra of
LZn(OTf)2 displayed a sharp peak at 1600−1660 cm−1 for
coordinated CN and an absorption at 1200−1260 cm−1 for
OTf−.37 Complexes incorporating the tetraphenyl-amine 3 and
various aldehydes were generated similarly, but not isolated,
and were also identified by ESI-MS.
5. Kinetic Studies of Esterolysis Catalyzed by LZn-
(OTf)2. The following LZn(OTf)2 were selected and evaluated
for catalytic activity, L= [2−4−4]-, [2−5−5]-, [2−6−6]-, [2−
9−9]-, [3−5−5]-, [3−6−6]-, [3−8−8]-, [3−9−9]. Most of
these candidates were initially detected by MS in the binary
The solvolytic rate constants depend markedly on the
catalyst structure (Figure 3, Table 3). The catalytic activities of
the imidazole-based complexes [2−4−4]-, [2−5−5]-, and [2−
6−6]-Zn(OTf)2 are similar, whereas the activity of benzimida-
zole derivative [2−9−6]Zn(OTf)2 is considerably greater.
Complexes derived from the tetraphenyl-diamine 3, [3−5−
5]-, [3−6−6]-, and [3−12−12]Zn(OTf)2, are 1−2 orders of
magnitude more active than those from diamine 2; but the
benzimidazole derivative [3−9−9]Zn(OTf)2 is less active,
comparable to [2−4−4]-, [2−5−5]-, and [2-6−6]-Zn(OTf)2.
The greater activity of benzimidazole-based complexes may be
the result of the lower basicity of the ligand (i.e., pKa 6.9 vs pKa
5.4),38 providing a more electrophilic LZn(sub)+ complex,
which enhances the susceptibility of the ester CO to
nucleophilic attack by MeOH. The greater activity of the
tetraphenyl derivatives is more surprising, since the electronic
differences between the parent H4- and the Ph4-ligands are
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Figure 13. Time-dependent 1H NMR spectra of R-1 ester reaction in CD3OD/CD2Cl2 (1:1) catalyzed by 1 mol % of [2−6−6]Zn(OTf)2; spectra,
recorded at 2 min intervals.
likely to be small. We speculate that the increased steric
demand of the latter ligand could accelerate a dissociative step
in the solvolytic mechanism, for example, facilitating chelate
arm decoordination to alleviate strain and enabling MeOH
coordination/activation with an enhanced reaction rate. We
observed significantly greater selectivity with some of the
present tetradentate-Zn catalysts compared to our previous
tridentate LZn-complexes.15 Regardless of cause, the (3-x-
y)Zn(OTf)2 complexes are among the more active esterolytic
Zn-catalysts reported to date.7,15,16
Key features of the kinetic enantioselectivity factors, kR/kS =
α, displayed by the various catalysts include (Table 3) the
following: (1) the values range from nil to moderate, with the
better selectivities coming from [2−6−6]-, [3−5−5]-, and [3−
Figure 14. Time-dependent PhCH(OD)Me formation in reaction of
R- and S-1 in CD3OD/CD2Cl2 (1:1) with 1 mol % [2−6−
6]Zn(OTf)2.
6−6]Zn(OTf)2 catalyzing the faster methanolysis of the R-
ester; and (2) the benzimidazole-derived catalysts [2−9−
9]Zn(OTf)2 and [3−9−9]Zn(OTf)2 exhibit a small kinetic
selectivity for the S-ester solvolysis. There appears to be a
modest correlation between the stereoselectivity and steric
demands of the ligand, for example, the t-Bu-imidazole-derived
complex [2−6−6]Zn(OTf)2 is more selective than the -NMe,
and -NPri derivatives, and the tetraphenyl-derived complexes
(entries 5−9) generally show greater enantioselectivity than
those derived from the diamine 2 (entries 1−4). Disappoint-
ingly, none of these catalysts exhibit the level of enantiose-
lectivity that would enable an effective kinetic resolution, for
example, α ≥ 10.6,10,39 However, the better selectivities
displayed by the present chiral complexes are comparable to
those reported previously for synthetic metal complex-based
esterolytic catalysts. What then may be the reason for the
modest chiral discrimination displayed by the present LZn
complexes? The possibility that this is the result of competing
catalysis by an achiral Zn-species such as Zn(solvent)(OTf)2
was evaluated (as per a reviewer’s suggestion). Indeed, it was
found that methanolysis of ester 1 is catalyzed by Zn(OTf)2 (in
the absence of a tetramine L) with a rate constant, k = 6.8 ×
Table 3. Rate Constants for Methanolysis of R- and S-1
a b
,
Catalyzed by L*Zn(OTf)2
entry
catalyst (loading)
kR (M−1 s−1
)
kS (M−1 s−1
)
kR/kS
1
2
3
4
5
[2−4−4]Zn(OTf)2 (1 mol %) 2.3 × 10−6
[2−5−5]Zn(OTf)2 (1 mol %) 2.0 × 10−6
[2−6−6]Zn(OTf)2 (1 mol %) 5.0 × 10−6
[2−9−9]Zn(OTf)2 (1 mol %) 2.6 × 10−5
2.3 × 10−6
2.0 × 10−6
2.4 × 10−6
2.8 × 10−5
3.5 × 10−5
1.0
1.0
2.1
0.93
2.3
[3−5−5]ZnOTf)2
8.3 × 10−5
1.1 × 10−4
7.9 × 10−5
4.4 × 10−6
2.5 × 10−5
(0.1 mol %)
6
7
8
9
[3−6−6]Zn(OTf)2
3.7 × 10−5
5.4 × 10−5
5.8 × 10−6
1.6 × 10−5
2.8
(0.1 mol %)
[3−8−8]Zn(OTf)2
1.4
(0.5 mol %)
[3−9−9]Zn(OTf)2
0.76
1.5
(0.5 mol %)
[3−12−12]Zn(OTf)2
(1 mol %)
a
[R- and S-13]0 = 10 mM, [catalyst] = 0.10 mM, 0.050 mM, and 0.010
b
mM in 1:1 CD3OD/CD2Cl2 (T = 292 K). Selected runs repeated in
triplicate gave rate constants with values within 5%.
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10−5 M−1 s−1, comparable to the complexes derived from 3 and
about 10-fold greater than by those derived from 2 (Table 3).
Nonetheless, the absence of MS-detectable free Zn species in
solutions of ligands 2 and 3 + Zn(OTf)2 (op cit) and the
proven high affinity binding of tetradentate amines for Zn(ii)
(Kf = 108−1011)31 provide evidence that unselective catalysis of
ester solvolysis by (solvated) zinc ion is unlikely to make a
significant contribution to the reaction rates and selectivity. A
more likely factor is imperfect transfer of chirality from the L-
Zn complexes to the bound transition state. Supporting this
notion, preliminary PM3 and DFT molecular modeling
calculations of selected diastereomeric ternary L*Zn-complexes
of R- and S-13 show small energy differences of 0−3 kcal.
One of the goals of this study was to assess the correlation
between the enantioselectivity of substrate and TSA-binding to
the L*Zn(OTf)2 complexes and their catalytic enantioselectiv-
ity. No appreciable substrate (1) binding selectivity was
detected with [2−6−6]Zn(OTf)2 which exhibits appreciable
kinetic selectivity. This supports the idea that stereoinduction
in the solvolytic reactions catalyzed by (L*)Zn(OTf)2 is
achieved in the tetrahedral transition state or intermediate
rather than from stereoselective substrate binding. This feature
contrasts with a report of MS-based selection Pd-catalysts for
allylic substitution in which intermediate stability correlated
inversely with regioselectivity.40 For a variety of reasons we
were only able to obtain both TSA-binding and kinetic
selectivity results with two complexes, [2−5−5]Zn(OTf)2
and [2−6−6]Zn(OTf)2. Although the latter does exhibit
both greater binding and kinetic selectivity than the former,
the configurational preferences of [2−6−6]Zn(OTf)2, S for
binding and R for reactivity, are opposite. Several explanations
for this disparity can be envisioned. One that we favor is that
the LZn(TSA)+ does not provide an accurate representation of
the electronic and geometrical characteristics of the reaction’s
stereodefining step. We note that pyridine-PO2(OR*)− is best
suited as a hydrolytic TSA (OH as attacking Nu) and does not
include a methoxy group on the P-atom that would mimic that
of the approaching MeOH involved in forming the tetrahedral
intermediate (B, Figure 15). Efforts are underway to prepare
and test the binding affinity and stereoselectivity of such a
phosphodiester (D).
libraries by ESI-MS analysis with enantiomeric R- and S-2-
pyridyl phosphonate TSA 13 show chiral discrimination via
formation of diastereomeric LZn(R/S-13)+ complexes with low
to moderate enantioselectivity ratios, kR/kS (α), ranging from
0.5 to 5.0, whereas templating with the enantiomeric substrates,
PyrCO2CH(OH)Ph (1), show negligible chiral recognition.
The rate constants for methanolysis of the R- and S-esters,
PyrCO2CH(OH)Ph, catalyzed by several BIN complexes vary
several fold over the set of L* and with enantioselectivity
factors ranging from 1.0 to 2.5. This dynamic combinatorial
approach to the generation and MS-screening of metal complex
libraries provides a new and convenient methodology for high
throughput catalyst discovery. Its capability for templating with
substrates, TSAs or product analogs can be the basis for
selection of metal complex catalysts with high activity or
selectivity.
EXPERIMENTAL PROCEDURES
■
Materials and General Methods. Commercially available
reagents were used as received. R- and S-1-Phenylethanol picolinic
acid ester (1) and R- and S-1-phenylethanol pyridine-2-phosphonic
acid ester (13) were prepared by literature procedures.41 (4R,5R)-2,2-
Dimethyl-1,3-dioxolane-4,5-dimethanamine (2) and (4R,5R)-bis-
(aminodiphenylmethyl)-2,2-dimethyl-1,3-dioxolane (3) were prepared
and purified by a literature procedure.30,42 The aldehyde precursors N-
isopropyl-imidazole, N-tert-butyl-imidazole, N-benzylimidazole, 4,5-
diphenylimidazole, and N-methyl-4,5-diphenylimidazole were pre-
pared by reported procedures.43,44 The heterocyclic aldehydes 5−9
were prepared by a modification of the procedure reported by
Katritsky45 (see Supporting Information).
Infrared spectra (4000−500 cm−1) were recorded as KBr pellets.
1H- (300 MHz), 13C- (60 MHz) NMR spectra were obtained and
referenced to TMS as internal standard on a Varian Mercury 300
spectrometer. The molecular mass of the compounds was determined
(methanol or acetonitrile solution) by the observed formula m/z peak.
Low resolution MS data were obtained on a Micromass/Waters
QTOF-1 equipped with an electrospray ionization source in the
positive ion mode. Nitrogen gas was used as a nebulizing and drying
gas with capillary voltage 3.0 kV, cone voltage ramp 10−85 V, source
block temperature 120 °C, desolvation temperature 150 °C, and
desolvation flow rate 200 L/h. High resolution MS Data were
collected and analyzed on an Agilent 6538 UHD Accurate Mass
QTOF equipped with an electrospray ionization source in positive ion
mode. Nitrogen gas was used as a nebulizing and drying gas with the
drying gas temperature of 325 °C and 10 L/min flow rate; the
fragmentor voltage was 160 V and capillary voltage 3500 V.
Preparation of LZn(OTf)2 Complexes. The synthesis of [Zn(2−
4−4)(OTf)2] (below) is typical of that used for all the complexes. The
diamine 2 (0.50 mmol) was dissolved in 25 mL of dry acetonitrile. To
this solution an acetonitrile solution of N-methylimidazole carbox-
aldehyde (1.0 mmol in 25 mL) was added, followed by zinc triflate
(0.50 mmol) dissolved in 10 mL of acetonitrile. The resulting mixture
was refluxed overnight, then the solvent was evaporated and the
residual solid was triturated with small portions of diethyl ether to
obtain the spectroscopically pure product.
Figure 15. Tetradentate zinc complexes with TSA 13 (B) and a
phosphodiester (D).
[Zn(2−4−4)(OTf)2]. ESI-HRMS (CH3CN) found: m/z = 557.0761,
+
calcd for C18H24N6O5S64ZnF3 = 557.0772; IR (KBr): 3392, 2991,
1635, 1500, 1425, 1259, 1163, 632; 1H NMR (CD3CN, δppm): 8.68 (s,
2H), 7.48 (d, 2H, J = 1.2 Hz), 7.19 (s, 2H), 4.15 (d, 2H, J = 11.1 Hz),
4.06 (d, 2H, J = 4.8 Hz), 4.0 (m, 2H), 2.84 (s, 4H), 1.44 (s, 6H).
[Zn(2−5−5)(OTf)2]. ESI-HRMS (CH3CN) found: m/z = 613.1396,
CONCLUSIONS
■
Individual and dynamic libraries of chiral tetradentate N4-
diimine-Zn(OTf)+ complexes have been prepared from
tartrate-derived diamines and various N-heterocyclic aldehydes.
ESI-MS analysis allows convenient determination of the
composition of the species in the library at equilibrium and
the change in library composition upon the addition of a
coordinating chiral substrate and enantiomeric phosphonate
TSAs. Binding studies of the (diimine)Zn(OTf)2 complex
+
calcd for C22H32N6O5S64ZnF3 = 613.1398; IR (KBr): 3400, 2989,
1631, 1485, 1269, 1163, 1028, 638; 1H NMR (CD3CN, δppm): 8.72 (s,
2H), 7.64 (d, 2H, J = 1.8 Hz), 7.28 (s, 2H) 4.89 (m, 2H), 4.17 (d, 2H,
J = 9.9 Hz), 4.06 (d, 2H, J = 1.8 Hz), 4.0 (m, 2H), 1.57, 1.55 (dd, 12H,
J = 1.2 Hz, 1.8 Hz), 1.45 (s, 6H).
[Zn(2−6−6)(OTf)2]. ESI-HRMS (CH3CN) found: m/z = 641.1717,
+
calcd for C24H36N6O5S64ZnF3 = 641.1711; IR (KBr): 3133, 2992,
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1630, 1520, 1437, 1240, 572; 1H NMR (CD3OD, δppm): 9.20 (s, 2H),
7.85 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 4.42 (d, 2H, J = 12.6
Hz), 4.13 (m, 4H), 1.84 (s, 18H), 1.64 (s, 6H).
Similarly, experiments with pairs of aldehydes (6,7; 5,9; 5,7; 6,9)
showed their competitive ability to form ternary [Zn(L)TSA]
complexes. ESI-MS analysis of library III (tetraphenyl-amine 3 +
aldehydes (4, 5, 6, 7, 8 and 9) and Zn(OTf)2) showed a variety of
binary zinc complexes. Among 21 possibilities, 10 binary complexes
were detected: [64Zn(3−4−5)(OTf)]+ (m/z = 889.2334), [64Zn(3−
4−9)(OTf)]+ (m/z = 911.2174), [64Zn(3−5−5)(OTf)]+ (m/z =
917.2637), [64Zn(3−5−9)(OTf)+ (m/z = 939.2482), [64Zn(3−9−
9)(OTf)]+ (m/z = 961.2335), [64Zn(3−9−7)(OTf)+ (m/z =
987.3320), [64Zn(3−7−7)(OTf)+ (m/z = 1013.2641), [64Zn(3−5−
8)(OTf)+ (m/z = 1041.2956), [64Zn(3−8−9)(OTf)]+ (m/z =
1063.2803), [64Zn(3−7−8)(OTf)+ (m/z = 1089.2945). Attempts to
template this library with R/S-TSA 13 in methanol resulted in rapid
precipitation as was observed with CH3CN, DMF, nitromethane, and
isopropanol, as well with a lower amount of TSA 13 (LZn/TSA
1.0:0.1).
Analysis of Substrate Selectivity by ESI-MS. In a typical
procedure 0.050 mmol of the diamine 2 or 3 and 0.10 mmol of N-t-
butylimidazole carboxyaldehyde (6) were dissolved in 2 mL of dry
CH3CN and then 0.05 mmol of Zn(OTf)2 was added and the resulting
solution was stirred overnight at rt. Next, 100 μL of a 0.05 mM
solution of Bu4NPF6 in CH3CN was added as an internal standard. A
0.05 mM solution of (1 mL) of the R- or S-substrate 1 was then added
to the above reaction mixture. After 1 h of stirring, a 220 μL stock
solution (A) was prepared by pipetting 20 μL from the above reaction
mixture and diluting it with 200 μL of CH3CN. Then, 220 μL of a
second stock solution (B) was prepared by pipetting 20 μL from stock
solution A and diluting it with 200 μL of CH3CN. Finally, 20 μL of
stock solution B was pipetted out and diluted with 200 μL of CH3CN
to obtain stock solution C. Solution C was analyzed by ESI-MS to
determine the formation of the substrate ternary complexes LZn(R- or
S-1). Initially, we observed an ion at m/z = 641.1, calculated for
[64Zn(2−6−6)(OTf)]+, C24H36N6O5F3S64Zn+: 641.17. After adding
the substrate 1 into the solution of binary complexes and stirring for
0.5 h at rt, ESI-MS analysis showed the appearance of a new set of
peaks centered at m/z 359.7, calculated for [(2−6−6)64Zn(1)]2+,
C37H49N7O464Zn2+/2: 359.5.
[Zn(2−9−9)(OTf)2]. ESI-HRMS (CH3CN) found: m/z = 657.1081,
+
calcd for C26H26N6O5S64ZnF3 = 657.1085; IR (KBr): 3393, 2988,
1
1638, 1495, 1272, 1033, 926, 746, 642, 573, 516; H NMR (CD3CN,
δppm): 9.0 (s, 2H), 7.85 (d, 2H, J = 8.7 Hz), 7.60 (d, 2H, J = 8.4 Hz),
7.43 (m, 4H), 4.28 (d, 4H, J = 9.9 Hz), 4.10 (s, 6H), 4.0 (m, 2H), 1.46
(s, 6H).
[Zn(3−5−5)(OTf)2]. ESI-HRMS (CH3CN) found: m/z = 917.2648,
+
calcd for C46H48N6O5S64ZnF3 = 917.265; IR (KBr): 3324, 1612,
1497, 1237, 1071, 1004, 888, 751, 710, 625, 574, 515; 1H NMR
(CD3CN, δ): 8.23 (s, 2H), 7.68−7.0 (m, 14H), 4.19 (s, 2H), 1.56 (d, J
= 6.6 Hz, 12H), 1.10 (s, 6H).
[Zn(3−6−6)(OTf)2]. ESI-HRMS (CH3CN) found: m/z = 945.2948,
+
calcd for C48H52N6O5S64ZnF3 = 945.2963; IR (KBr): 3147, 2985,
1658, 1606, 1469, 1379, 1244, 1159, 1095, 1028, 877, 758, 702, 636,
1
514 cm−1; H NMR (CD3CN, δ): 8.2 (s, 2H), 7.51−7.24 (m, 20H),
4.20 (s, 2H), 1.18 (s, 3H), 1.58 (s, 18H), 1.56 (s, 3H).
[Zn(3−8−8)(OTf)2]. ESI-HRMS (CH3CN) found: m/z =
+
1165.3267, calcd for C66H56N6O5S64ZnF3 = 1165.3276; IR (KBr):
1
3060, 1603, 1465, 1222, 1019, 768, 697, 634, 574 cm−1; H NMR
(CD3CN, δ): 8.80 (m, 1H), 7.54−7.19 (m, 40H), 3.79 (m, 2H), 3.54
(s, 3H), 3.26 (s, 3H), 1.10 (s, 6H).
[Zn(3−9−9)(OTf)2]. ESI-HRMS (CH3CN) found: m/z = 961.3076,
+
calcd for C50H44N6O5S64ZnF3 = 961.2337; IR (KBr): 3063, 1615,
1
1295, 1165, 1019, 750, 701, 631, 574, 515 cm−1; H NMR (CD3CN,
δ): 7.51−7.32 (m, 20H), 7.12−7.13 (m, 4H), 6.98 (m, 4H), 3.92 (s,
3H), 3.69 (s, 3H), 3.30 (d, J = 3.3 Hz, 2H), 1.10 (s, 6H).
Job Plot Analysis. A 10 mM stock solution of the LZn(OTf)2
complex [Zn(2−6−6)(Otf)2] was prepared in 1.5 mL of CD3OD; a
10 mM stock solution of S-TSA was prepared in 1.5 mL of CD3OD.
The NMR Job plot samples were prepared by combining the zinc
complex and S-TSA stock solutions in the proportions 450 μL/50 μL,
350 μL/150 μL, 250 μL/250 μL, 150 μL/350 μL, 50 μL/450 μL,
keeping the total concentration of L64Zn(OTf)2 plus S-TSA 13
constant at 10 mM. Samples were analyzed by 1H NMR monitoring of
the chemical shift (δ) of the imine proton signals as a function of the
Zn/TSA ratio. The plots of Δδ × [cat]0 versus [cat]0/([cat]0 + [S-
13]0) for [Zn(2−6−6)(Otf)2] is given in Figure 6. A separate Job plot
study was conducted as above for the S-substrate ester 1 in CD3CN
with the Zn-complex [Zn(2−6−6)(OTf)2]. The Job plot graph
showed an upward rise at 9:1 ratio of substrate to Zn.
Analysis of LZn(OTf)+ and LZn(TSA-13)+ Complexes by ESI-
MS. Phase 1: Each building block (0.05 mmol of chiral diamine and
0.1 mmol of aldehydes) was dissolved in 4 mL of CH3OH. Then 0.05
mmol of Zn(OTf)2 was added to the above stirring mixture and the
mixture allowed to equilibrate overnight at room temperature. Next,
100 μL of 0.05 mM solution of Bu4NPF6 in MeOH was added as an
internal standard. A 220 μL stock solution A was prepared by pipetting
20 μL from the above library mixture and diluting it with 200 μL of
CH3OH. Then, 220 μL of a second stock solution (B) was prepared
by pipetting 20 μL from stock solution A and diluting it with 200 μL of
CH3OH. Further, 20 μL of stock solution B was transferred into
another vial and diluted with 200 μL of CH3OH to obtain stock
solution C. Solution C was screened by ESI-MS to detect the binary
[Zn(L)(OTf)2] complex formation. Phase 2: To the above library
aliquots, 1 mL of 0.05 mM of S-TSA or R-TSA 13 was added to form
ternary complex libraries and kept stirring for 24 h at rt. ESI-MS
samples were prepared by making different stock solutions (A, B, C) as
described above and then the final solution C was taken for ESI-MS
analysis, to monitor ternary [LZn(13)]+ formation/amplification.
Time dependent ternary [Zn(2−4, −8, −10)(TSA-13)] complex
formation was monitored by the above procedure sampling at 2, 4.5,
27, and 35 min to establish attainment of equilibrium. The calculated
relative abundance of the ternary complexes with enantiomeric R- and
S-13 = (ion count of peak/ion count of internal standard)/sum over
all ions of (ion count of peak/ion count of internal standard). The
ratio of these values for the enantiomeric 13 complexes is the
stereoselectivity factor, α.
Kinetics for Methanolysis of R- and S-Picolinate Ester (1)
Catalyzed by Zn-Imine Complexes. The methanolysis of R- and S-
1-phenylethanol picolinic acid ester (PEP, 1) was carried out
separately with the same substrate/catalyst concentrations; the
reported rate constants (Table 3) are from single runs. A 10 mM
stock solution of catalyst was prepared in 0.3 mL of CD3OD/CD2Cl2
(1:1); 1.0 and 0.1 mM stock solutions of catalyst were prepared by
serial dilutions of the stock solution with 1:1 CD3OD/CD2Cl2. The
samples for NMR reaction monitoring were prepared either from R- or
S-ester (10 mM) by dissolving each into an NMR tube in 1 mL of
CD3OD/CD2Cl2 (1:1); then 100 μL of the catalyst solution (10 mM,
1
1.0 mM or 0.1 mM) was added. H NMR spectra were recorded at
two minute intervals (T = 292 K) while monitoring the disappearance
of the substrate methyl signal at 1.95 ppm and the growth of the
product alcohol methyl peak at 1.69 ppm. Initial rates were determined
by plotting the peak integrals versus time (s) for the initial 10−20%
conversion; the slopes of these plots divided by the initial
concentrations of PEP (1) and the LZn(OTf)2 complex provided
the second order rate constants listed in Table 3.
ASSOCIATED CONTENT
■
S
* Supporting Information
Synthesis of heterocyclic aldehydes and their characterization
by 1H, 13C NMR, ESI-MS spectra of new compounds are given.
The chiral diamines were synthesized using literature
procedures and their spectral characterization is provided.
ESI-MS spectra from selected library screenings are also given.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Phone: 1-405-235-3696. Fax: 1-405-325-6111. E-mail:
knicholas@ou.edu.
■
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Dr. Steven Foster (O.U. Mass Spectrometry Center)
for assistance with the ESI-MS studies.
■
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