Autoamplification-Enhanced Oxidative Kinetic Resolution of sec-Alcohols and Alkyl Mandelates, and its Kinetic Model

Article abstract of DOI:10.1002/cctc.201800180

In this contribution, the new dynamic nonlinear effect in asymmetric catalysis is discussed, manifesting itself in the oxidative kinetic resolution (OKR) of racemic secondary benzylic alcohols and alkyl mandelates with H₂O₂ in the presence of chiral Mn-based catalyst, with the apparent selectivity factor (k_rel) of the resolution being nonconstant over the reaction course. Typically, the initial growth of k_rel is changed into decay at high conversions. In this contribution, we demonstrate the oxidative kinetic resolution of various substrates bearing sec-alcoholic moieties, with the k_rel varying in different manners with increasing substrate conversion. We also present the predictive kinetic model of OKR with participation of asymmetric autoamplification. The influence of substrate and catalyst structure, as well as solvents and additives, on the behavior of k_rel variation, is discussed.

Full text of DOI:10.1002/cctc.201800180

Accepted Article
Title: Autoamplification-enhanced Oxidative Kinetic Resolution of sec-
Alcohols and Alkyl Mandelates, and its Kinetic Model
Authors: Evgenii Talsi and Konstantin Petrovich Bryliakov
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10.1002/cctc.201800180
ChemCatChem
Autoamplification-enhanced Oxidative Kinetic Resolution of sec-Alcohols and Alkyl
Mandelates, and its Kinetic Model
Evgenii P. Talsi,[a,b] Konstantin P. Bryliakov[a,b]
*
[a] Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russian Federation
[b] Boreskov Institute of Catalysis, Pr. Lavrentieva 5, Novosibirsk 630090, Russian Federation
E-mail: bryliako@catalysis.ru
Abstract
In this contribution, the new dynamic nonlinear effect in asymmetric catalysis is discussed,
manifesting itself in the oxidative kinetic resolution (OKR) of racemic secondary benzylic alcohols
and alkyl mandelates with H2O2 in the presence of chiral Mn based catalyst, with the apparent
selectivity factor (krel) of the resolution being nonconstant over the reaction course. Typically, the
initial growth of krel is changed into decay at high conversions. In this contribution, we
demonstrate the oxidative kinetic resolution of various substrates bearing sec-alcoholic moieties,
with the krel varying in different manners with increasing substrate conversion. We also present the
predictive kinetic model of OKR with participation of asymmetric autoamplification. The
influence of substrate and catalyst structure, as well as solvents and additives, on the behavior of
krel variation, is discussed.
1
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Introduction
Enantiopure aryl alkyl alcohols and β-hydroxy esters are valuable building blocks for the
construction of natural products, chiral ligands, auxiliaries, catalysts, and biologically active
compounds.[1] One of the basic synthetic strategies leading to enantioenriched substances bearing
secondary alcoholic moieties relies on the catalyzed kinetic resolution approaches.[2] Recently, in the
framework of our efforts to develop novel biomimetic catalysts for the catalytic asymmetric
synthesis of chiral, including bioactive, organic compounds,[3] we have reported that chiral
manganese aminopyridine complexes can act as catalysts for the oxidative kinetic resolution (OKR)
of racemic 1-arylalkanols with the environmentally benign oxidant H2O2.[4] It is archetypical for
manganese aminopyridine based asymmetric oxidation catalysts to require co-catalytic additives,
usually carboxylic acids, for the effective H2O2 activation.[5] Crucially, complex 1 (Scheme 1), the
best of the series, could efficiently catalyze the OKR of 1-arylalkanols without any co-catalytic
additives, with the apparent OKR selectivity factor, krel, substantially increasing over the reaction
course. The nature of this phenomenon was disclosed in a mechanistic study:[4] the substrate affected
the stereochemical course of the reaction via coordination to the Mn center and thus formation of
two diastereomeric catalytically active sites, having different reactivities toward the (R)- and (S)-
enantiomers of the alcohol substrate. With increasing conversion, the less reactive substrate
enantiomer predominated, eventually leading to progressive amplification of the resolution
stereoselectivity (Scheme 1).
The observed effect has been unprecedented in the literature; it ranks with such phenomena
as asymmetric autocatalysis,[6] asymmetric autoinduction,[7] and autocatalysis (first reported by
Menschutkin in 1882)[8] in a more general sense. To unambiguously identify this novel dynamic
non-linear effect (NLE)[9] in asymmetric catalysis, we have proposed the term asymmetric
autoamplification.[4] From the mathematical perspective, dynamic nonlinear effects in catalysis,
2
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10.1002/cctc.201800180
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such as autocatalysis, asymmetric autocatalysis, asymmetric autoinduction, and asymmetric
autoamplification have the same characteristic feature that the corresponding reaction rate equations
are fundamentally nonlinear. At the same time, the above phenomena exhibit themselves in
chemically (and kinetically) different ways, which difference is schematically illustrated in Figure 1.
In contrast to asymmetric autoinduction, which is the case when the chiral product of the
reaction modifies the stereochemical course of the reaction by changing the nature of the reagent or
the catalyst,[6b,7a,9d] and asymmetric autocatalysis, which is a special case of autoinduction,
consisting in the self-reproduction of a chiral catalyst,[9d] asymmetric autoamplification deals with
the effect of the reactant(s) (not products!) on the stereochemical course of the reaction. Herewith,
we propose the following formal definition of asymmetric autoamplification: “Asymmetric
autoamplification is the case when chiral substrate enhances its enantiomeric (or
diastereomeric) purity over the course of a catalytic reaction, by changing the nature of the
catalyst”. We point out the fundamental differences between asymmetric autoamplification and
asymmetric autoinduction with amplification of enantiomeric excess:[9d,10] in the former case, (1) the
catalytic reaction is assisted by the substrate (not product), and (2) the reaction product is not
necessarily chiral (Figure 1). By the proposed definition, it is assumed that asymmetric
autoamplification may be the case in reactions resting on the different reactivities of two
stereoisomeric substrates, so kinetic resolution reactions are the potential natural habitat of
asymmetric autoamplification effects.
In this contribution, the influence of asymmetric autoamplification on the oxidative kinetic
resolution of sec-alcohols has been studied in detail, using a broader selection of different
substrates. In some cases, the apparent selectivity factor, krel, has been experimentally observed to
vary non-monotonously over the reaction course, the initial growth of krel changing into decay at
high conversions.
3
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Previously, in the series of pioneering works, Ismagilov,[11a] Kagan,[11b] and Singleton[11c]
with co-workers proposed the kinetic models for the kinetic resolution reactions influenced by
nonlinear effects stemming from the presence of non-racemic chiral catalysts, i.e. due to the
interaction between two molecules of the chiral catalyst, affording a set of diastereomeric catalytic
species exhibiting different reactivities toward the substrate enantiomers. Herewith, we propose a
complementary non-linear kinetic model for the kinetic resolutions affected by asymmetric
autoamplification arising from the interaction between the reactant(s) and the chiral catalyst. The
simplified model has analytical solution and allows extracting kinetic parameters from
experimental data.
Scheme 1. Two competitive pathways in the OKR of sec-alcohols in the presence of catalyst 1.
Diastereomeric active species have different selectivity factors (kSrel > kRrel). Ar = aryl.
4
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Figure 1. The difference between asymmetric autocatalysis, asymmetric autoinduction, and
asymmetric autoamplification. A is substrate, B is reactant, C – catalyst, P – product. Asterisks
indicate chiral reactants/catalysts/products.
Results and Discussion
Kinetic model of OKR with asymmetric autoamplification
A series of substrates have been resolved with H2O2 in the presence of complex 1; the results are
presented in Table 1. In brief, enantioenriched sec-alhohols having up to 95 % ee have been
obtained at 67-75 % conversion levels. We notice, however, that the formal selectivity
factors krel listed in Table 1 correspond to the reported conversions only; in fact, the selectivity
factors were nonconstant over the reaction course (Figure 2). Given the proposed mechanism shown
in Scheme 1, the formal kinetic model has been developed.
Let us consider the following scheme for the oxidative kinetic resolution of sec-alcohols;
hereinafter, “R”, “S”, “Cat”, and “K” stand for the (R)-alcohol, (S)-alcohol, chiral catalyst, and
ketone product, respectively:
(1)
(2)
5
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Table 1. Kinetic resolution of p-substituted 1-phenylethanols in the presence of Mn complexes.[a]
HO
Y
HO
Y
HO
Y
Y
O
1 (0.1 mol. %)
+
CH3CN
(additive)
H2O2
+
X
X
X
X
-10 °C
major
minor
Conversion (%)[b] ee (%)[b] krel
[c]
Entry
1
Substrate
74
68
73
72
95
95
86
86
6.6[4]
8.8[4]
4.7
2
3
4
4.9
5
6
67
73
76
82
4.6
4.2
7
8
9
67
75
60
72
73
57
4.1
3.2
3.8
[a] For reaction conditions see SI. [b] Determined by chiral HPLC as reported.[5c] [c] The formal
stereoselectivity factor was calculated as krel = ln[(1-c)(1-ee)]/ln[(1-c)(1+ee)],[9c] where c is the
conversion of the alcohol and ee is the enantiomeric excess of the alcohol.
6
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10
10
9
8
7
6
5
4
3
2
1
0
100
90
100
90
80
70
60
50
40
30
20
10
0
A
1-p-tolylethanol
B
1-phenylethanol
9
8
7
6
5
4
3
2
1
0
80
70
60
50
40
30
krEel1/ 2
kr0el
krEel1/ 2
kr0el
= 4.5
= 3.6
20
10
0
0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0
0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0
conversion
conversion
10
9
8
7
6
5
4
3
2
1
0
100
100
90
10
9
8
7
6
5
4
3
2
1
0
butyl mandelate
C
D
1-phenylpropanol
90
80
70
60
50
40
30
20
10
0
80
70
60
50
40
30
20
10
krEel1/ 2
kr0el
krEel1 / 2
kr0el
= 3.4
= 4.0
0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0
0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0
conversion
conversion
[9c]
Figure 2. Plots of the apparent krel (blue) and enantiomeric excess (red) vs. conversion for the
oxidation of 1-phenyl ethanol (A), 1-p-tolyl ethanol (B), butyl mandelate (C), 1-phenylpropanol (D)
with H2O2 in the presence of catalyst 1. Theoretical dependencies of krel vs. conversion, fitted to
experimental data (for details see SI), extrapolated to low and high conversions (green). Theoretical
dependencies of ee vs. conversion, simulated using fitted parameters (black).
In addition to reactions (1) and (2), one has to take into account complexation between the
chiral catalyst and the substrate enantiomers (eq. (3) and (4)), and the oxidation reaction mediated
by the substrate-complexed catalyst, Cat·S and Cat·R (eq. (5)-(8)):
(3)
(4)
7
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10.1002/cctc.201800180
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(5)
(6)
(7)
(8)
The overall rates of consumption of the (R)- and (S)-alcohol, respectively, will be
= −k [Cat][S] − k R [Cat ⋅ R][S] − k S [Cat ⋅S][S]
d[S]
(9)
S
S
S
dt
d[R]
= −k [Cat][R] − k S [Cat ⋅S][R] − k R R [Cat ⋅ R][R]
(10)
R
R
dt
Given the complexation equilibria (3) and (4) and the mass balance for catalyst
Cat0 = [Cat] + [Cat·R] + [Cat·S], one can calculate the concentrations of all forms of the catalyst:
Cat0 KR [R]
Cat0
Cat 0 KS [S]
[Cat ⋅R] =
[Cat] =
, [Cat ⋅S] =
,
,
(11)
1+ KR [R]+ KS [S]
1+ KR[R]+ KS [S]
1+ KR [R] + KS [S]
which in combination with eq. (9) and (10) leads to the following equation
kR [R] + KS k S R [S][R] + K k R R [R][R]
d[R]
R
=
(12)
kS [S] + KR k R S [R][S] + K k S S [S][S]
d[S]
S
This non-linear differential equation contains too many kinetic parameters to be reliably
evaluated from the experimental data such as krel vs. conversion curve. For the purposes of this
study, eq. (12) can be simplified by considering extreme case of significant asymmetric
autoamplification, in particular, by neglecting the reactions shown in eq. (5) (assuming that Cat·S is
very poorly reactive toward (S)-alcohol) and eq. (8) (assuming [R] < [S], or even [R] << [S], which
is the case at sufficiently high conversions, such that the [R]2 term could be neglected as compared
8
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with [S]·[R]). In effect, eq. (12) is reduced to the following simplified equation with separable
variables
kR [R] + KS k S R [S][R]
d[R]
d[S]
≈
,
(13)
kS [S] + KR k R S [R][S]
which (in case of initially racemic sec-alcohol, [R]0 = [S]0 = C0) has the following solution (for more
detail see Supporting Information):

















[S]
C0
1
1
[R]
C0
[R]
C0








= a1LambertW  exp
1+ a2 Ln
− a3 1−
 ,
(14)




a
a
1






1





kR
C0 k S R K
kS
KR k R
KS k S
S
where a1 =
, a2 =
, a3 =
. We notice that the ratio of kR/kS, which
C0 k S R K
R
S
S
corresponds to the selectivity factor without asymmetric autoamplification (kr0el ), can be found as
a1 kR
=
, while 1/a3 affords the crucial parameter of asymmetric autoamplification, KSkS /KRkR .
R
S
a2 kS
Indeed, if the OKR occurs exclusively via autoamplified pathway, the equation (13) is reduced to
(
KS k S R [S]
[R]
)
d[R]
d[S]
[R]
[S]
≈
= krEel
(15)
(
KR k R S [R]
[S]
)
where in parentheses is the effective selectivity factor of the autoamplified OKR pathway,
k E = KSkS [S]/KRkR [R]. The k E / k0 is therefore the key characteristic of the asymmetric
R
S
rel
rel
rel
autoamplification for each particular substrate: krEel / kr0el > 1 corresponds to autoamplification,
whereas krEel / kr0el < 1 should reflect the so far hypothetic case of autodepletion. However, krEel is
dependent on the ratio of concentrations [S]/[R], which may vary substantially over the reaction
course. As a uniform approach, hereinafter we will use krEel values calculated at 50 % substrate
9
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conversions ( krEel ); in turn, the krEel / kr0el ratio will be used as a measure for the asymmetric
1/ 2
1/ 2
autoamplification effect for each particular substrate.
Equation (14) can be used to fit the experimental krel vs. conversion dependencies (for details
see SI). The relationship (14) contains three parameters, incorporating the kinetic constants for the
various oxidation pathways (1) – (8). Depending on the particular set of parameters, the following
possibilities can be considered (Figure 3): autoamplified-only OKR (the case of strong substrate
coordination to the catalyst) (Figure 3A); “standard” OKR with substantial contribution of
autoamplification (Figure 3B); OKR without autoamplification (Figure 3C); and OKR with weak
substrate coordination (Figure 3D,E). In the latter case, the krel may either monotonously decrease
throughout the reaction (Figure 3E), or pass through a maximum and further decline (Figure 3D).
12
A
10
8
6
4
2
B
C
D
E
0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0
conversion
Figure 3. Theoretically predicted dependence of the apparent krel vs. conversion for the model cases
of nearly autoamplified-only OKR (a1= 0.02, a2= 0.02, a3= 0.2) – (A), “standard” OKR with
substantial contribution of autoamplification (a1= 0.4, a2= 0.1, a3= 0.2) - (B), OKR without
autoamplification (a1= 100, a2= 21, a3= 0.2) - (C), and two cases of OKR with weak substrate
coordination: (a1= 1.5, a2= 0.5, a3= 0.2) - (D) and (a1= 1.4, a2= 0.6, a3= 0.07) - (E).
10
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Based on the solution (14), the experimental krel vs. conversion curves for the OKR of
several substrates have been fitted (Figure 2; for more curves see Figure S1, SI), to afford the
parameters a1, a2, a3, and the asymmetric autoamplification effect values. Although the fit was not
ideal (particularly at high conversions, when krel passes through the maximum and begins to
decline), the theoretically predicted dependencies of krel and ee upon conversion demonstrated good
qualitative agreement with the experimental data up to rather high conversion levels (60…80 %,
Figure 2B,D). At the same time, in some cases, the observed drop of the apparent krel at high
conversions was not well reproduced by the theoretically predicted dependence (Figure 2A,C),
which may be due to (1) lower ee measurement precision at high ees, and (2) influence of some
other, so far undisclosed factors, operative at high conversion levels.
Substrate and external-ligand dependence of the asymmetric autoamplification effect
So far, the behavior of experimental krel (Figure 2) has been typical for the case of “standard” OKR
with substantial contribution of autoamplification (Figure 3B). At the same time, since the OKR
with asymmetric autoamplification implies coordination of the substrate molecule to the
catalytically active site, the autoamplification apparently should be dependent on the ability of the
substrate to coordinate and, specifically, on the size of the sec-alcohol. In particular, one could
expect that for bulkier substrates, the autoamplification should be less significant, owing to steric
restrictions for the substrate coordination to manganese. In full agreement with this prediction, the
variation of krel with conversion in the presence of catalyst 1 was more pronounced for smaller
substrates (such as 1-p-tolyl ethanol and 1-phenyl ethanol) and less significant for bulkier substrates
(Figure 4A).
A remarkable exception is the OKR of the bulky 1-(2-naphthyl)ethanol: in this case, the krel
substantially declined over the reaction course (Figure 4A, wine curve). Tentative explanation of
11
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this anomality may be the following: only one of the enantiomers (namely (R)-, the more reactive
one), readily coordinates to the catalytically active sites, while the coordination of the other ((S)-)
enantiomer is hampered owing to steric restrictions. With increasing conversion, the concentration
of the (R)-enantiomer, as well as the coordinated catalyst Cat·R, declines; in effect, the kinetic
resolution stereoselectivity decreases monotonously, approaching that for the substrate-free catalyst.
On the other hand, one could expect that externally added abundant coordinating ligand
(e.g. carboxylic acid) should block the substrate coordination to the metal center and so suppress the
autoamplification. Indeed, when excess of acetic acid was added, the resulting krel vs. conversion
plots (Figure 4B) were either characteristic of weak substrate coordination cases (butyl mandelate,
1-phenyl ethanol) or reflected the “OKR without autoamplification” cases for 1,2-diphenylethanol
and methyl mandelate – in the latter two cases, the krel remained virtually constant (krel = 1.50…1.40
and 2.09…2.06, respectively) throughout the reaction (Figure 4B). These data open the way for
manipulating the contribution of asymmetric autoamplification: upon demand, the latter may be
attenuated or completely suppressed by adding sufficient amount of coordinating ligand.
The effect of several solvent on the variation of krel with conversion has been tested. In
acetone, the catalyst system 1/H2O2 retained autoamplification behavior (Figure 4C). Very recently,
thrifluoroethanol has been proposed as solvent in Mn-catalyzed C-H oxidation reactions;[5g]
herewith, oxidative kinetic resolution of 1-phenylethanol in this solvent has occurred without
variation of krel, presumably owing to predominant coordination of thrifluoroethanol to Mn in the
active sites, thus blocking the substrate coordination. On the other hand, in aprotic water-immiscible
solvents (either polar nitromethane or less polar ethyl acetate), the krel also did not significantly vary
throughout the reaction (Figure 4C).
12
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9
8
7
6
5
4
3
2
1
A
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
conversion
B
4
3
2
1
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
conversion
C
7
6
5
4
3
2
1
CH3CN
acetone
ethyl acetate
CH3NO2
trifluoroethanol
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
conversion
Figure 4. Plots of the apparent krel vs. conversion for the oxidation of various substrates with H2O2
in the presence of catalyst 1 – (A), in the presence of catalyst 1 and excess AcOH – (B), and in
different solvents – (C). 1-p-tolyl ethanol (magenta), 1-phenyl ethanol (black), n-butyl mandelate
(green), methyl mandelate (orange), 1,2-diphenylethanol (blue), p-t-butylphenyl-1-ethanol (red), 1-
(2-naphthyl)ethanol (wine).
13
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Conclusions
Chiral Mn aminopyridine complex 1 has been shown to catalyze the oxidative kinetic resolution of
secondary benzylic alcohols and alkyl mandelates with H2O2 without co-catalytic additives,
affording chiral alcohols with up to 95 % ee, which is the commonly accepted level for practical
applications. The distinctive feature of the above kinetic resolutions is that the apparent selectivity
factor (krel) of the resolution is nonconstant over the reaction course due to the asymmetric
autoamplification effect.[4] The latter is the case when the enantiomers of the substrate coordinate to
the catalytically active sites, which results in the formation of two diastereomeric catalytically active
species, having different reactivities toward the (R)- and (S)-enantiomers of the substrate. It is a new
dynamic nonlinear effect, related to asymmetric autocatalysis and asymmetric autoinduction with
amplification of enantiomeric excess, but not identical with either of those.
The contribution of asymmetric autoamplification in the oxidative kinetic resolution of sec-
alcohols and alkyl mandelates has been found to be substrate-dependent. For relatively small
secondary alcohols (1-phenylethanol, 1-p-tolylethanol), the krel monotonously increases over the
reaction course up to substrate conversions of ca. 70 %. For bulkier alcohols or alkyl mandelates,
the growth of krel is less pronounced and changes into decay at moderate conversions of ca. 50-60
%. A remarkable exception is the bulkiest 1-(2-naphthyl)ethanol: in this case, the krel monotonously
declines over the reaction course. The addition of acetic acid, which is a widely accepted co-
catalytic additive for Mn catalyzed biomimetic oxygenations, suppresses or completely switches off
the autoamplification; a similar effect can be achieved by replacing acetonitrile as solvent with
trifluoroethanol, nitromethane, or ethyl acetate.
The predictive nonlinear kinetic model of the oxidative kinetic resolution with participation
of asymmetric autoamplification has been presented. The proposed model has analytical solution
and allows extracting kinetic parameters from experimental data.
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ChemCatChem
Although the as yet documented krel values are moderate (≤ 8.8), we notice that Mn-
aminopyridine catalyzed OKR of substrates bearing sec-alcoholic moieties has so far been the only
example of catalytic reactions with asymmetric autoamplification. Further studies are underway,
aimed at finely tuning the aminopyridine ligand structure in order to enhance the stereorecognition
of the enantiomers of sec-alcohols.
Associated content
Materials and methods, catalytic procedures, HPLC separation details, HPLC traces, solution of
differential equation (13), additional fitting details. This information is available free of charge via
the Internet at http://pubs.acs.org/.
Author information
Corresponding author
E-mail: bryliako@catalysis.ru.
ORCID
Evgenii P. Talsi: 0000-0003-0756-1401
Konstantin P. Bryliakov: 0000-0002-7009-8950
Notes
The authors declare no competing financial interest.
Acknowledgments
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ChemCatChem
This work was conducted within the framework of the budget project for the Boreskov Institute of
Catalysis. All necessary chemicals and consumables have been purchased with the aid of the
Russian Foundation for Basic Research (project 16-29-10666).
Keywords
Asymmetric autoamplification; chirality; hydrogen peroxide; kinetic resolution; manganese
References
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FULL PAPER
Substrate-affected asymmetric
catalysis: the stereochemical
outcome of the oxidative kinetic
resolution of secondary benzylic
alcohols and alkyl mandelates in the
presence of chiral Mn-aminopyridine
complexes is influenced by the
substrate coordination to the
Evgenii P. Talsi, Konstantin P.
Bryliakov*
12
autoamplified-only
OKR
Page No. – Page No.
10
8
Autoamplification-enhanced
Oxidative Kinetic Resolution of sec-
Alcohols and Alkyl Mandelates, and
its Kinetic Model
OKR with contribution
of autoamplification
6
4
regular OKR (without
autoamplification)
catalytically active sites. The kinetic
treatment of this new dynamic
nonlinear effect - asymmetric
2
0
20
40
60
80
100
conversion, %
autoamplification - is presented.
19
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