In-Situ Monitoring of Enantiomeric Excess during a Catalytic Kinetic Resolution

Article abstract of DOI:10.1021/acscatal.8b01411

Vibrational Circular Dichroism combined with FTIR spectroscopy (VCD-IR) is demonstrated as a viable tool for the in situ measurement of enantiomeric excess during asymmetric catalytic transformations. Employing the Jacobsen (salen)Co-catalyzed hydrolytic kinetic resolution of racemic epoxides as a proof-of-concept case study, methodology is developed to monitor the enantiomeric excess of the epoxide substrate as a function of conversion of the limiting reactant, water. Comparison of results for monomeric and oligomeric catalysts probes the molecularity of the catalyst by investigating nonlinear effects in catalyst enantiopurity. These results are in excellent agreement with previous mechanistic investigations of this reaction based on kinetic measurements and computational studies.

Full text of DOI:10.1021/acscatal.8b01411

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Article
In-Situ Monitoring of Enantiomeric Excess
During a Catalytic Kinetic Resolution
Matthew P. Mower, and Donna G Blackmond
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01411 • Publication Date (Web): 23 May 2018
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In-Situ Monitoring of Enantiomeric Excess During a Catalytic
Kinetic Resolution
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Matthew P. Mower, Donna G. Blackmond*
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037 USA
ABSTRACT: Vibrational Circular Dichroism combined with FTIR spectroscopy (VCD-IR) is demonstrated as a viable tool for
the in-situ measurement of enantiomeric excess during asymmetric catalytic transformations. Employing the Jacobsen (salen)Co-
catalyzed hydrolytic kinetic resolution of racemic epoxides as a proof-of-concept case study, methodology is developed to moni-
tor the enantiomeric excess of the epoxide substrate as a function of conversion of the limiting reactant, water. Comparison of re-
sults for monomeric and oligomeric catalysts probes the molecularity of the catalyst by investigating nonlinear effects in catalyst
enantiopurity. These results are in excellent agreement with previous mechanistic investigations of this reaction based on kinetic
measurements and computational studies.
Keywords: enantiomeric excess, vibrational circular dichroism, kinetic resolution, nonlinear effects, reaction progress
INTRODUCTION
In-situ monitoring of reaction progress has become a stand-
ard tool in mechanistic analysis of catalytic reactions, particu-
larly in the pharmaceutical industry. The ability to obtain a
rapid scan of concentration profiles spanning the full conver-
sion regime led to the development of Reaction Progress Ki-
netic Analysis (RPKA),1 a streamlined methodology for de-
termining concentration dependences to formulate a reaction
rate law as well as for probing process robustness. Using
RPKA, extensive information content is accessible from fewer
separate experiments than is typical in classical kinetic analy-
sis. This information may then be used to develop a mecha-
nism, to optimize a reaction in batch, or to design an efficient
flow process.
(1)
We report the development of vibrational circular dichroism
(VCD-IR) as a tool for temporal monitoring of ee. We chose
the Jacobsen (salen)Co-catalyzed hydrolytic kinetic resolution
of racemic epoxides5 (Scheme 1) as a test case for proof-of-
concept because of its practical importance and its well-
studied mechanism. The VCD-IR technique successfully mon-
itors both ee and conversion over the course of this reaction, as
validated by sampling and GC analysis. We were also able to
confirm mechanistic insights into catalyst speciation for mon-
omeric and oligomeric catalysts by probing for nonlinear ef-
fects of catalyst enantiopurity6 on differential kinetic enantio-
meric enhancement (DKEE).7 These results are in good
agreement with previous experimental rate measurements,
kinetic modeling, and DFT calculations.8 This work supports
the general use of VCD-IR as an in-situ tool for temporal
monitoring of enantiomeric excess.
In a similar vein, one might envision the development of in-
situ means of measuring reaction variables other than concen-
tration dependences, for example temperature, as in adiabatic
reaction calorimetry2 or temperature-scanning reaction proto-
cols.3 One variable that has so far eluded general development
of a non-invasive in-situ monitoring methodology is enantio-
meric excess in asymmetric catalytic transformations.4
A
number of compelling cases exist for monitoring ee as a func-
tion of time. For example, temporal erosion in ee is a common
indication of catalyst degradation, where in-situ monitoring of
ee could serve as an early alert and be useful in modeling this
behavior. Other important cases where ee changes with time
include racemization or epimerization and kinetic resolution.
In a kinetic resolution, the two enantiomers of a substrate react
at different rates typically characterized by the selectivity fac-
tor, krel, described in terms of conversion (c) and ee for the
case of initially racemic substrate (eq 1). In-situ temporal
monitoring of ee with reaction progress could present a more
accurate means of measuring krel, provide valuable mechanis-
tic insights and allow process improvements.
R kR → PR
S kS → PS
kR
kS



ln 1− c 1− ee
(
)(
)
)

krel
=
=


ln 1− c 1+ ee
(
)(


1
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Scheme 1. Hydrolytic Kinetic Resolution of Propylene
Page 2 of 7
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Epoxide Catalyzed by (Salen)Co Complexes.
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BACKGROUND
Vibrational circular dichroism (VCD)9,10 extends the well-
established method of electronic circular dichroism (ECD)
from the UV/Vis to the IR region of the electromagnetic spec-
trum. One of the biggest advantages of expanding the probe to
this region is the ability to detect a wider range of molecules,
most notably including those without aromatic groups. While
ECD has been employed for ee measurement during high
throughput screening,11-13 that approach is not compatible with
the goal of unperturbed in-situ kinetic monitoring. VCD-IR
spectra are highly sensitive to both the chirality and the con-
formation of the species being detected. The two enantiomers
of a compound yield identical IR spectra, and their VCD spec-
tra will be equal in intensity but opposite in sign, as shown in
Figure 1a for the model system α-pinene. The experimentally
observed VCD spectrum is the sum of the spectra from all
different conformers, weighted by their relative distribution.
This allows conformational information to be extracted from
VCD spectra in addition to sense of chirality. VCD-IR has
been used with great success over the past several decades for
the determination of absolute configuration (AC),14 made pos-
sible by improvements in the availability of high quality ab
initio density functional theory calculations of VCD spectra.
VCD spectroscopy has been used in a wide range of physical
organic chemistry studies of small molecules as well as to
probe supermolecular chirality.15
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intensity = [R] – [S]
b
VCD spectra can provide a quantitative measurement of ee
when coupled with vibrational spectra in the infrared region.
The VCD signal intensity is proportional to the difference in
concentration of the two enantiomers in the sample, while the
IR signal is proportional to the sum of the two, as shown in
Figure 1b and 1c. The enantiomeric excess may be calculated
by combining the data from VCD and FTIR spectra as shown
in eq 2.
c
intensity = [R] + [S]
from VCD
   
R − S
(
(
)
)
(2)
   
ee =
   
R + S
from FTIR
   
Figure 1. a) VCD spectra of neat enantiopure R and S α-pinene;
b) VCD spectra of mixtures of R-α-pinene with increasing
amounts of S-α-pinene; c) FTIR spectrum of neat α-pinene.
A number of early studies used offline VCD analysis of gas
phase samples to monitor chiral reactions.16 Continuous meas-
urement of ee in a dynamic system, analogous to the use of
traditional IR spectroscopy to monitor concentration continu-
ously over a reaction time course, has only been explored to
date in a small number of simple systems. Nafie and cowork-
ers followed the pseudo-racemization of 2,2-dimethyl-1,3-
dioxolane-4-methanol in a range of solvents by VCD-IR.17
The extended reaction times allowed for excellent signal in
this system containing only one chiral reactant or product.
Grinberg and coworkers monitored the kinetics of racemiza-
tion of an imidazoline, a class of molecules that are valuable
building blocks for chiral ligands and for pharmaceuticals.18
VCD-IR coupled with DFT calculations provided a detailed
mechanistic picture of the reaction and demonstrated the role
of aromatic substituents in the racemization process. Lüdeke
and coworkers monitored the hydrolysis of a Ni sparteine
complex using a custom VCD system employing a quantum
cascade laser.19
These studies were carried out in less complex chiral envi-
ronments than many asymmetric reactions, and these results
inspired us to develop VCD-IR as a mechanistic tool to probe
complex multi-step asymmetric catalytic reactions such as the
hydrolytic kinetic resolution (HKR) of epoxides shown in
Scheme 1. The HKR has been demonstrated to be bimolecular
in catalyst, with the rate-determining step found to be reaction
between one catalyst molecule bound to the epoxide (3·E) and
a second catalyst molecule bound to the nucleophile, water
(3·N), yielding a bimolecular transition state (Scheme 2a) and
a second order dependence on catalyst concentration. Jacob-
sen and coworkers showed that reaction rates could be greatly
accelerated by linking two catalyst molecules at an optimal
distance from one another, as in 4, creating a high effective
molarity for the rate-determining step (Scheme 2b), which is
first order in the dimeric catalyst 4.
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The involvement of two chiral catalyst molecules in a single
tion provides trends for individual reaction components and
the ee of propylene oxide, which was validated by comparison
to chiral chromatographic analysis of sample aliquots.15 Once
the method is validated in this way, further reactions may be
carried out under different conditions with a single aliquot
taken at the end of spectral data collection serving to normal-
ize the traces to the conversion and ee value of the reaction
endpoint.
1
2
3
4
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step for the monomeric catalyst 3 raises the possibility of non-
linear effects in catalyst enantiopurity, which has been exten-
sively studied by the Jacobsen group.7 While epoxide and wa-
ter substrates bind identically to either hand of the catalyst,
only the “matched” interaction between epoxide- and water-
bound catalyst molecules of like chirality are productive in the
reaction. For monomeric catalyst 3, this self-selection results
in a nonlinear effect where the observed selectivity in the ki-
netic resolution is not proportional to enantiomeric excess of
the monomeric catalyst. For the dimeric catalyst 4, where each
dimer contains two catalyst molecules of the same chirality,
the reaction selectivity remains proportional to the enantio-
meric excess of 4. These mechanistic insights have been ob-
tained through kinetic and computational studies and discrete
measurements of enantiomeric excess. The aim of our study is
to determine whether temporal probing of enantiomeric excess
in the reaction of Scheme 1 by VCD-IR bears out this mecha-
nistic picture, thus providing a proof-of-concept for its use as
an in-situ mechanistic probe.
RESULTS AND DISCUSSION
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The kinetic resolution of Scheme 1 was monitored by VCD-
IR using both the monomeric catalyst 3 and the dimeric cata-
lyst 4 at varying values of enantiomeric excess. Validation of
the methodology for determining ee is shown in Figure 2 by
comparison to ee determined by chiral HPLC of discrete sam-
ples. Temporal ee profiles are shown in Figure 3 for reactions
carried out with the two catalysts at a range of catalyst ee val-
ues. As shown by the slopes of these curves, the rate of change
of ee in racemic substrate 1 in the kinetic resolution of Scheme
1 decreases with decreasing catalyst ee for both the monomer-
ic catalyst 3 and the dimeric catalyst 4.
12
10
8
1.0
propylene oxide 1
0.6
ee
ee
0.2
6
-0.2
-0.6
-1.0
4
2
propylene glycol 2
Scheme 2. Elementary steps and transition states in the
HKR of Scheme 1 catalyzed by a) momeric catalyst 3 and
b) dimeric catalyst 4.
0
0
50
100
150
200
250
time (min)
EXPERIMENTAL
Both the reactant and the product of the kinetic resolution of
Scheme 1 are chiral, as is the catalyst; we carried out prelimi-
nary studies of a number of different racemic epoxides that
have been shown to undergo the HKR before choosing the
propylene oxide system. Features of the molecule including its
rigidity and number of conformers affet the VCD signal. The
chosen system shows both a strong VCD signal for the epox-
ide reactant 1 as well as a nearly silent VCD spectrum for the
product diol 2.20 Catalyst loadings were chosen to provide
similar temporal progress curves for the monomeric catalyst 3
(5.7 mM) and the dimeric catalyst 4 (1.1 mM) to catalyze the
reaction of 10.8 M rac-1 0.1 equiv. product propylene glycol
and 0.6 equiv H2O. A small amount (0.05 equiv.) of enanti-
opure epoxide was added to rac-1 in order to improve the
VCD signal of low ee data at the beginning of the reaction.20
The HKR reaction is carried out in a recycling batch reactor in
which the reaction solution is circulated through a flow cell
mounted within the VCD spectrometer. Simultaneous collec-
tion of both IR and VCD spectra is possible using the Chiral-
IR-2X instrumental platform developed by BioTools, Inc.
Spectra are acquired and co-added over blocks of five-minute
duration that optimizes the balance between spectral and tem-
poral resolution. These data are exported into MATLAB for
analysis. Chemometric interrogation of the VCD and IR spec-
tra using a Multivariate Curve Resolution (MCR) decomposi-
Figure 2. Temporal profiles from the reaction of Scheme 1 using
catalyst 3. Racemic reactant 1 (blue symbols) and product 2 (or-
ange symbols) from FTIR spectra of the reaction using (R,R)-3.
Enantiomeric excess (ee) of 1 from VCD-IR (black lines) com-
pared with ee from analytical sampling from aliquots (gray sym-
bols) using (R,R)-3 (top) and (S,S)-3 (bottom), validating the
technique for in-situ ee measurement in the reaction of Scheme
1.20
The selectivity factor for a kinetic resolution given in eq 1
may be written in general terms as the ratio of the rate constant
for the major pathway to that of the minor pathway, as in eq 3.
Solving for the rate of change of the enantiomer of 1 on the
major pathway compared to that of the enantiomer of 1 on the
minor pathway gives the classic expression for kinetic resolu-
tion of eq 4. Combining VCD and IR data allows us to calcu-
late the selectivity factor for this reaction. By fitting the major
and minor epoxide concentration profiles for both catalysts 3
and 4 gives krel = 32 for enantiopure catalysts in the reaction of
Scheme 1 under the conditions employed in these studies.20
kmajor
kminor
(3)
krel
=
kmajor
kminor
3





1
 major
1
 minor
 
1
=



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



 
1
 
  minor,0 

major,0 

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(4)
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Values for krel may also be calculated for each scalemic run
for both catalyst 3 and catalyst 4. We employ the Singleton
treatment where a variable termed differential kinetic enanti-
omeric enhancement, DKEE, has been defined (eq 5).
1
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kmajor − kminor
krel −1
catalyst 3
(5)
DKEE =
=
kmajor + kminor krel +1
catalyst 4
1.0
0.8
0.6
0.4
0.2
a
0
0.2
0.4
catalyst ee
0.6
0.8
1
Figure 4. DKEE (eq 5) plotted as a function of catalyst ee in the
reaction of Scheme 1 catalyzed by 3 (blue circles) and 4 (green
circles). Dashed line shows the linear relationship. Solid blue line
is the fit to the Kagan ML2 model with K=4 and g=0.20
0.0
0
50
100
150
200
250
time (min)
1.0
0.8
0.6
0.4
0.2
The parameters of the Kagan ML2 model have been re-
interpreted in the context of the mechanism of the reaction of
Scheme 1.7 That model was developed for the case of dimeric
catalysts, where two chiral ligands L bind to one or two metal
centers M. When both hands of the ligand, LR and LS, are pre-
sent, the possibility exists for both homochiral (MLRLR and
MLSLS) and heterochiral (MLRLS) catalytic species to be
formed. The parameter K represents the equilibrium composi-
tion of these species. While the homochiral species will act as
catalysts to give identical rates and opposite product ee values,
the heterochiral species as catalyst may exhibit a different
relative rate, characterized by the parameter g, and will pro-
duce racemic product. The case of K = 4, g = 0 in the standard
ML2 model describes the stochastic formation of species (i.e.,
no preference between forming heterochiral or homochiral
species) where the heterochiral species is inactive as a catalyst.
In the case of the reaction of Scheme 1 catalyzed by mono-
meric 3, rather than considering bimetallic intermediate spe-
cies, the model describes the potential for homochiral or het-
erochiral transition states rather than stable species. In this
context, K = 4 implies that matched and mismatched 3·E and
3·N species may encounter each other with equal preference,
while g = 0 implies that only the matched encounters result in
a productive reaction. The results of Figure 4 are in excellent
agreement with the findings of the Jacobsen group.
b
0.0
0
50
100
150
200
250
time (min)
Figure 3. Fraction enantiomeric excess from VCD-IR meas-
urements for the reaction of Scheme 1 carried out using a)
(R,R)-3 and b) (R,R)-4 at varying ee values: red = 100% ee;
orange: 79% ee 3, 75% ee 4; yellow: 59% ee 3, 50% ee 4;
green: 39% ee 3, 38% ee 4; blue: 20% ee 3, 19% ee 4; indigo:
0% ee 3, 1% ee 4.20
The relationship between DKEE and catalyst ee affords a
means to analyze nonlinear effects of catalyst enantiopurity in
kinetic resolution in a similar graphical treatment as that de-
veloped by Kagan for asymmetric catalysis. When the krel val-
ues for catalysts 3 and 4 are determined for the reactions at
different catalyst ee values and plotted as DKEE vs. catalyst
ee, the relationships shown in Figure 4 are revealed.17 The
dimeric catalyst exhibits linear behavior in DKEE with respect
to catalyst ee, as shown by the fit of the points to the dashed
line. By contrast, the monomeric catalyst exhibits a positive
nonlinear effect. Fitting these data fit to the Kagan ML2 model
with the parameters K=4 and g = 0 gives the blue line shown
in Figure 4.
For the dimeric catalyst 4, since each catalyst molecule con-
tains two sites with the same chirality, mismatched encounters
cannot occur, and product ee remains proportional to catalyst
ee. This difference between the two catalysts is also manifest-
ed by differences in selectivity and rates for scalemic catalysts,
as highlighted in Figure 5. Selected ee data from Figure 3 for
both catalysts are plotted together as a function of conversion
in Figure 5a, while Figure 5b plots product formation vs time
for both catalysts at 40% ee.
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ies successfully confirm complex mechanistic details of the
1
2
3
4
5
6
Jacobsen hydrolytic kinetic resolution previously obtained
through experimental kinetic studies and computational inves-
tigations. This work promises to add an important process
analytical tool for mechanistic understanding and for reaction
monitoring and process improvement in asymmetric catalytic
transformations.
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Supporting Information. Experimental details and details for
analysis of VDC spectra. This information is available free of
charge on the ACS Publications website.
1.0
0.8
0.6
0.4
0.2
0.0
a)
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enantiopure
AUTHOR INFORMATION
Corresponding Author
* Blackmond@scripps.edu
40% ee
ACKNOWLEDGMENT
racemic
The authors gratefully acknowledge funding from the Simons
Foundation Simons Collaboration on the Origins of Life (SCOL
287625). Detailed discussions with L. Nafie and R. Dukor are
gratefully acknowledged.
0.0
0.2
0.4
0.6
fraction conversion
REFERENCES
b)
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catalyst 4
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time (min)
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1997).
Figure 5. a) Fraction enantiomeric excess plotted as a function of
conversion of substrate 1 in the reaction of Scheme 1 catalyzed by
enantiopure (blue symbols), 40% ee (green symbols) and racemic
(magenta symbols) 3 (filled circles) and 4 (open circles); b) prod-
uct 2 concentration as a function of time for catalysts 3 and 4 at
40% ee.
4
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Nafie, L. A. Determination of Enantiomeric Excess in Samples of
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Dichroism Spectroscopy: Simulation of Real-Time Reaction
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lysts 3 and 4 show similar trends for product ee as a function
of conversion, the scalemic case shows a divergence between
the two catalysts. A greater change in ee observed as conver-
sion increases for the monomeric catalyst 3 than for the dimer-
ic catalyst 4. This difference may be understood in the context
of the nonlinear effect observed for 3, with the reaction em-
ploying the monomeric catalyst exhibiting higher ee at a given
conversion compared to that for 4. Figure 5b, showing that the
dimeric catalyst 4 shows a higher rate of reaction compared to
3 as the reaction progresses, is also consistent with theoretical
predictions of the ML2 model.6b A positive nonlinear effect, or
asymmetric amplification, comes at the expense of reaction
rate as the unproductive mismatched interactions effectively
decrease the active catalyst concentration.
5
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Catalysis. Acc. Chem. Res. 2000, 33, 402–411.
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Resolutions. J. Am. Chem. Soc. 1999, 121, 9307–9312.
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Co(Salen) Complexes: Synthetic Applications and Mechanistic
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CONCLUSIONS
VCD-IR spectroscopy has been demonstrated to provide a
practical means of monitoring enantiomeric excess over the
course of an asymmetric catalytic transformation. These stud-
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20 See Supporting Information.
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ACS Catalysis
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7
OH
H2O
R,R-Co(salen)
O
O
+
OH
(+/-)
1.0
1
2
a)
0.8
0.6
0.4
0.2
0.0
8
9
enantiopure
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12
13
14
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17
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30
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
40% ee
racemic
0.0
0.2
0.4
0.6
fraction conversion
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