Catalytic, enantioselective, intramolecular carbosulfenylation of olefins. mechanistic aspects: A remarkable case of negative catalysis

Article abstract of DOI:10.1021/ja413270h

In the course of developing an enantioselective, Lewis base/Bronsted acid co-catalyzed carbosulfenylation of alkenes, a seemingly impossible conundrum arose: How could a catalyst inhibit a stoichiometric reaction? Despite the observation of very good enantioselectivities, the rate of the uncatalyzed reaction (i.e., no Lewis base) was found to be comparable to or slightly faster than that of the catalyzed process. A combination of detailed kinetic and spectroscopic studies revealed that the answer is not the direct involvement of the Lewis base catalyst, but rather the secondary consequences of its conversion to the catalytically active sulfenylating agent. Generation of the chiral sulfenylating species is accompanied by the formation of equimolar amounts of sulfonate ion and phthalimide which serve to buffer the remaining Bronsted acid and thus inhibit the racemic background reaction. Thus, the actual background reaction operative under catalytic conditions is not well mimicked by simply removing the catalyst.

Full text of DOI:10.1021/ja413270h

Article
pubs.acs.org/JACS
Open Access on 02/18/2015
Catalytic, Enantioselective, Intramolecular Carbosulfenylation of
Olefins. Mechanistic Aspects: A Remarkable Case of Negative
Catalysis
Scott E. Denmark* and Hyung Min Chi
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States
S
* Supporting Information
ABSTRACT: In the course of developing an enantioselective,
Lewis base/Brønsted acid co-catalyzed carbosulfenylation of
alkenes, a seemingly impossible conundrum arose: How could
a catalyst inhibit a stoichiometric reaction? Despite the
observation of very good enantioselectivities, the rate of the
uncatalyzed reaction (i.e., no Lewis base) was found to be
comparable to or slightly faster than that of the catalyzed
process. A combination of detailed kinetic and spectroscopic
studies revealed that the answer is not the direct involvement
of the Lewis base catalyst, but rather the secondary
consequences of its conversion to the catalytically active
sulfenylating agent. Generation of the chiral sulfenylating
species is accompanied by the formation of equimolar amounts
of sulfonate ion and phthalimide which serve to buffer the remaining Brønsted acid and thus inhibit the racemic background
reaction. Thus, the actual background reaction operative under catalytic conditions is not well mimicked by simply removing the
catalyst.
as part of our general program in Lewis base activation of Lewis
acids, we were interested in a more fundamental understanding
of the role of all reaction components and the mechanistic
underpinnings of this type of catalysis.
INTRODUCTION AND BACKGROUND
■
1. Brønsted Acid−Lewis Base Co-catalytic Carbo-
sulfenylation of Alkenes. Recently published studies from
these laboratories detail the optimization and development of a
catalytic, enantioselective carbosulfenylation of alkenes using
electron-rich arenes as the nucleophilic partner (Scheme 1).1 In
the course of optimization of this process, it was discovered that
the enantioselectivity was not reliably reproduced from
orienting experiments (0.2 mmol) to descriptive scale (1.0
mmol). Consideration of the experimental variables that could
be responsible led to detailed reevaluation of the role of the
Brønsted acid co-catalyst, methanesulfonic acid (MsOH).
Foregoing studies in these laboratories on the related
heterofunctionalization of alkenes revealed the need for a
Brønsted acid co-catalyst to enable Lewis base activation of
both Group 16 and Group 17 electrophiles.2 However, in none
of these previous studies was the Brønsted acid dependence
found to be problematic and, in general, a full equivalent with
respect to the substrate could be employed without affecting
reproducibility. For the carbosulfenylation, empirical optimiza-
tion outlined in the preceding studies1 led to the use of 0.75
equiv of ethanesulfonic acid (EtSO3H) for all preparative
experiments. Satisfactory rates and reproducible enantio-
selectivities were found.
2. Objectives of This Study. The goal of this study was to
provide a detailed understanding of the mechanism of catalysis
of carbosulfenylation using the combination of chiral Lewis
base (S)-1 and Brønsted acids MsOH and EtSO3H with 2 and
substrate 3 (Scheme 1). To gain insight into this process, a
number of different spectroscopic and kinetic studies were
carried out to provide answers to the following questions: (1)
What are the rates of the catalyzed and uncatalyzed reactions
promoted by varying amounts of MsOH and EtSO3H? (2)
What is the protonation state of the sulfenylating agent under
catalytic conditions with MsOH and EtSO3H? (3) What is the
resting state of (S)-1 under catalytic conditions? (4) What is
the structure of the catalytically active species? (5) What is the
protonation state of the catalyst in the absence of sulfenylating
agent 2? The answers to these questions are provided below
and together provide a refined picture of the mechanism of
catalysis and a striking illustration of how seemingly contra-
dictory results can be understood in the light of thorough
mechanistic analysis.
Despite the successful deployment of these conditions for the
method, it was nonetheless of significant interest to elucidate
the basis for the heightened sensitivity of this particular
sulfenofunctionalization toward the Brønsted acid. In addition,
Received: January 3, 2014
Published: February 18, 2014
© 2014 American Chemical Society
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Scheme 1
Figure 1. Reactions with MsOH (1.0 equiv). (a) Rate profile for catalyzed cyclization with 0.1 equiv of (S)-1. (b) Rate profile for uncatalyzed
cyclization.
Surprisingly, the uncatalyzed reaction is significantly faster
than the catalyzed process and follows apparent zeroth-order
kinetic behavior. Curiously, the formation of 4 was accom-
panied by formation of 5, the product of proton-initiated
cyclization (ca. 15%). Thus, the competitive production of
racemic 4 at a rate comparable to that of the catalyzed process
clearly reveals the problems associated with irreproducible
enantioselectivity in the presence of MsOH.
RESULTS
■
1. Rates of Catalyzed and Uncatalyzed Reactions. To
establish the rates of the Lewis base catalyzed cyclization and
the uncatalyzed cyclization in the presence of both Brønsted
acids, MsOH and EtSO3H, NMR kinetic analysis with an
internal standard was performed at −20 °C for the reaction of
alkene 3 to produce 4. Reactions were carried out at 0.2 M
concentrations.3
The time courses for the corresponding reactions in the
presence of EtSO3H are similar to those in the presence of
MsOH. The catalyzed cyclizations at various loadings of
EtSO3H (Figure 2a) display normal first-order kinetic behavior,
but in this case, the initial rates of the reaction at all loadings of
EtSO3H are similar. Interestingly, the enantiomeric composi-
tion of 4 eroded only slightly at higher loadings of EtSO3H.5
The uncatalyzed reactions of 3 in the presence of varying
amounts of EtSO3H (Figure 2b,c) mimic the results obtained
with MsOH. Interestingly, with 1.00 equiv of EtSO3H, the rate
of formation of 4 was comparable to that in the presence of
(S)-1 and again displayed zeroth-order kinetic behavior. Here
again, 5, the product of proton-initiated cyclization, was formed
in minor amounts.
Four critical insights were gained from the low-temperature
NMR kinetic studies: (1) Both MsOH and EtSO3H are
competent Brønsted acids for both the catalyzed and the
uncatalyzed sulfenocarbocyclizations. (2) Proton-initiated
cyclization to form 5 was observed in the absence of catalyst
(S)-1 but not in its presence. (3) Overall first-order kinetic
1.1. Observations on the Purity of Alkylsulfonic Acids. As
part of the optimization experiments designed to elucidate the
origin of the variable enantioselectivity, the purity (i.e.,
hydration level) of the sulfonic acids was investigated. The
hydration level of the highly hygroscopic alkylsulfonic acids
1
could be specified by integration of the OH signal in the H
NMR spectra in CDCl3. It was found that the hydration level
significantly influenced the rate and enantioselectivity of the
cyclization such that high hydration levels (e.g., 20 mol %
water) led to slower, but more selective reactions. Accordingly,
to vouchsafe the quality of the sulfonic acid for reproducibility,
both MsOH and EtSO3H were rigorously dried by established
procedures (see Supporting Information), and the hydration
levels were checked by 1H NMR integration on a regular basis.
All of the experiments described below were performed with
MsOH and EtSO3H of specified purity.
1.2. Reaction Rates at 0.2 M. The time course for the
catalyzed reaction with MsOH at the preparative reaction
concentration (Figure 1a) reveals clean and high-yielding
conversion of 3 to 4, reaching completion in 12 h.4
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Figure 2. Reactions with EtSO3H (X equiv). (a) Rate profile for catalyzed cyclization with 0.1 equiv of (S)-1. (b) Rate profile for formation of 4 in
the uncatalyzed cyclization. (c) Rate profile for formation of 5 in the uncatalyzed cyclization.
Table 1. Determination of Equilibrium for Formation of 6 at 8.3 μM in (S)-1
reagents (equiv)
PhthSPh
31P NMR (δ, ppm)
i-Bu cat.
EtSO3H
at −20 °C
at −50 °C
95.2 (br)
1.0
1.0
1.0
10.0
10.0
10.0
0.0
1.0
2.5
95.0
94.9 (br)
94.3 (br), 64.7 (br)
95.4 (br), 63.9 (br)
(ratio = 1.00:0.91)
1.0
1.0
1.0
10.0
10.0
10.0
5.0
7.5
63.7 (br)
63.7
64.0
64.0
63.9
10.0
63.6
behavior was observed under catalysis by (S)-1. (4) Overall
zeroth-order kinetic behavior was observed for the formation of
4 in the absence of (S)-1.3
equilibrium formation of that species. Thus, low-temperature
NMR experiments were undertaken under catalytic conditions
without substrate (2/(S)-1, 10.0:1.0) with varying amounts of
EtSO3H at −20 °C (8.3 μM in (S)-1). At this temperature, the
exchange between (S)-1 and 6 was too fast to allow accurate
integration, so the experiments were repeated at −50 °C (Table
1).6 Under these conditions, both species could be detected
simultaneously, and this revealed that the catalyst becomes
saturated as 6 somewhere between 2.5 and 5.0 equiv of EtSO3H
In addition to these important insights, the kinetic analysis
also raises interesting questions: (1) How is it possible to
obtain enantiomerically enriched 4 if the background,
uncatalyzed, racemic reaction is comparable to (EtSO3H) or
faster than (MsOH) the reaction catalyzed by chiral Lewis base
(S)-1? (2) How can the formation of 5 in the background
reaction be reconciled with its absence in the catalyzed
reactions? Answers to these questions require a better
understanding of what actually constitutes the background
reaction and will be addressed in the following sections.
2. Catalyst Resting State and Titration Studies.
2.1. Identifying and Quantifying the Catalytically Active
Species. Foregoing studies with (S)-1 established that the
catalytically active sulfenylating agent is formed by sulfenyl
group transfer from 2 to the selenophosphoramide mediated by
a Brønsted acid. In view of the unusual dependence of the rate
of catalyzed sulfenocarbocyclization on acid loading (Figure
2a), it was of interest to establish the magnitude of the pre-
Table 2. Determination of Equilibrium for Formation of 6 at
25 μM in (S)-1
reagents (equiv)
i-Bu
cat.
ratio of 31P NMR signals at 95 and 64 ppm
PhthSPh EtSO3H
(−57 °C)
1.0
1.0
1.0
1.0
1.0
10.0
10.0
10.0
10.0
10.0
1.0
2.5
3.0
3.5
4.0
3.12:1.00
1.00:1.86
1.00:4.07
1.00:24.88
1.00:54.49
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Figure 3. Calculation of Keq for 6 assuming solvent-separated ion pair structure.
Figure 4. Calculation of Keq for 6 assuming intimate ion pair structure.
(with respect to (S)-1). Repeating the titration experiments at
2.3. Protonation State of Phenylsulfenophthalimide (2)
and the Catalyst ((S)-1). To gain insight into the curious
behavior of noncatalyzed cyclizations, the protonation states of
(S)-1 and 2 were determined by VT-NMR experiments. The
exchange rate between 2 and 2·H+RSO3− was sufficiently rapid
at −20 °C (125 MHz 13C) to allow observation of a sharp
singlet for the carbonyl groups that shifted from 167.8 ppm (no
RSO3H) to 168.9 ppm (10.0−15.0 equiv of RSO3H, Figure 5a).
These data were fitted to a curve with nonlinear regression
(single-site total binding model). Extrapolation of the curve for
−57 °C and at higher concentration (25 μM in (S)-1) allowed
a more accurate determination of the saturation point (Table
2). Thus, approximately 4.0 equiv of EtSO3H was needed to
convert ca. 98% of (S)-1 into 6, whereas with 2.5 equiv of
EtSO3H only 65% of (S)-1 was converted.
2.2. Calculation of Equilibrium Constants (Keq). Equili-
brium constants were calculated for the two preceding
experiments both at the 2.5 equiv data points. Calculations
were carried out assuming that the catalytically active species 6
exists either as a solvent-separated ion pair (Figure 3) or as an
intimate ion pair (Figure 4). Solving the equations at two
concentrations for the tight ion pair afforded the same
equilibrium constant, whereas solving for the solvent-separated
ion pair did not. Thus, it can be safely (and logically) concluded
that 6 is a tight ion pair in dichloromethane under the reaction
conditions.
MsOH gave 169.2 ppm as the chemical shift of 2·H+RSO3 ,
−
whereas doing the same for EtSO3H gave 169.0 ppm. These
extrapolated values lead to a single, apparent Keq = 3.63 M−1 for
MsOH and Keq = 2.05 M−1 for EtSO3H (Kd = 0.276 0.018 M
for MsOH and Kd = 0.488
0.049 M for EtSO3H). As
expected, the Keq value for MsOH is larger than that for
EtSO3H, because the ability of MsOH to protonate 2 is greater
than that of EtSO3H. By using the average of the extrapolated
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Figure 5. Titration curves for protonation of 2 with MsOH and EtSO3H.
Figure 6. Reactions with MsOH (1.0 equiv) and Bu4N+OMs−. (a) Rate profile for formation of 4 in the uncatalyzed cyclization. (b) Rate profile for
formation of 5 in the uncatalyzed cyclization.
chemical shifts of 2·H+RSO3 , the mole fraction of 2·H+RSO3
The results were striking: whereas 0.1 equiv of Bu4N+OMs−
slows the formation of 4 (but not 5), 0.2 equiv of Bu4N+OMs−
was able to almost completely shut down the formation of 4
and 5 in the presence of 1.0 equiv of MsOH. This observation
implies that the actual background reaction operating under
catalytic conditions is not accurately represented by simply
omitting the catalyst. Moreover, reconsideration of the
components present under catalytic conditions reveals that
the actual amount of MsOH available is only 0.9 equiv and that
0.1 equiv of phthalimide is also present, both as a consequence
of the formation of 6. Figure 7a shows the rate profile for the
uncatalyzed reaction with 0.9 equiv of MsOH and 0.1 equiv of
Bu4N+OMs−; Figure 7b shows the rate for the same
uncatalyzed reaction but with also 0.1 equiv of phthalimide.
Here again, suppression of the formation of 4 is striking,
illustrating that both methanesulfonate and phthalimide are
serving as buffers to attenuate the acidity of MsOH in the
medium. Figure 7c shows the superposition of all of these
experiments.
−
−
present at various loadings of acid could be calculated (Figure
5b); at 1.00 equiv of acid, 2·H+RSO3 is present at 41 mol %
−
with MsOH and 26 mol % with EtSO3H. These numbers
represent a significant amount of an active, achiral sulfenylating
agent that is responsible for the background reaction. However,
given the high enantioselectivities observed, the actual amount
of 2·H+RSO3− must be significantly less, the reason for which is
addressed below.
The protonation of catalyst (S)-1 was examined briefly.
Addition of 1.0 equiv of EtSO3H to a 0.1 mM solution of (S)-1
in CHCl3 had no effect on the 31P NMR chemical shift,
indicating a negligible degree of protonation.
3. Effect of the Presence of Sulfonate Anion on the
Rate of the Uncatalyzed Reaction. The realization that (1)
formation of catalytically active species 6 is quantitative under
the catalytic reaction conditions, (2) sulfenylating agent 2 is
partially protonated under these conditions, and (3) both of
these species carry sulfonate counterions led to the recognition
that the action of the remaining Brønsted acid could be
attenuated by the buffering effect of the sulfonate. Thus, a
modified version of the background reaction was formulated in
which the amounts of 6 and protonated 2 formed under
catalytic conditions were mimicked by adding varying amounts
of tetrabutylammonium mesylate (Bu4N+OMs−) (Figure 6).
It is now easy to see how a catalyzed reaction (black line) can
be slower than the corresponding uncatalyzed reaction (red
line) and still give rise to high enantioselectivities. One must
consider the circumstances under which the uncatalyzed
reaction is proceeding under the conditions of the catalyzed
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Figure 7. (a) Rate profile for the uncatalyzed reaction with 0.9 equiv of MsOH and 0.1 equiv of Bu4N+OMs−. (b) Rate profile for the uncatalyzed
reaction with 0.9 equiv of MsOH, 0.1 equiv of Bu4N+OMs−, and 0.1 equiv of phthalimide. (c) Superposition of all reactions with MsOH; only
formation of 4 is depicted.
process. Simply removing the catalyst is not sufficient to
accurately mimic those conditions.
1.2. Effect of Brønsted Acid on the Rate and
Enantioselectivity of the Sulfenocarbocyclization. The use
of MsOH (1.0 equiv) in the catalytic sulfenocarbocyclization
led to a rapid consumption of the alkene, leveling off at 98.5%
conversion at 12 h to afford 4 with a 75:25 er (Figure 1a). In
the absence of catalyst (S)-1, the reaction profile showed
zeroth-order decay, leveling off at >99% conversion at 3 h.9
Under these conditions, the product composition was ca. 91% 4
and 8% 5.
The use of EtSO3H in varying stoichiometries led to very
similar reaction profiles albeit at overall lower rates compared
to MsOH. The sulfenocarbocyclization of 3 proceeded with
normal first-order kinetics to afford 4 with highly reproducible
and higher enantioselectivities (ca. 92.5:7.5 er) (Figure 2a).
With 1.0 equiv of EtSO3H the rates of the catalyzed and
uncatalyzed reactions are comparable, leveling off at 98.6%
conversion of 3 at 24 h with (S)-1 and 99.3% conversion at 12
h without (S)-1. Here again, the uncatalyzed reaction is
competitive at 1.00 and 0.75 equiv of EtSO3H (Figure 2b).10
The reason for the difference between MsOH and EtSO3H will
be discussed below in the section on protonation equilibria with
2.
1.3. Effect of Brønsted Acid on the Resting State of the
Catalyst. The unusual similarity of the rate profiles for the
catalyzed sulfenocarbocyclization in the presence of various
amounts of EtSO3H (Figure 2a) stimulated an investigation
into the effect of the Brønsted acid on the conversion of catalyst
(S)-1 into the catalytically active sulfenylating agent 6. Low-
temperature 31P NMR titration experiments revealed that
catalyst (S)-1 becomes saturated as 6 with ca. 4.0 equiv of
EtSO3H and 10.0 equiv of 2 with respect to (S)-1 (i.e., 0.40
equiv with respect to 2 and substrate 3 under catalytic
conditions). Thus, the similarity of rates for 1.00, 0.75, and 0.50
equiv of EtSO3H and the lower rate for 0.25 equiv can be
readily understood from the amount of active sulfenylating
agent 6 present. Above 0.4 equiv of EtSO3H, the catalyst is
saturated, and thus the rate has reached a maximum.
An additional insight into the nature of the active
sulfenylating agent was secured by taking advantage of the
fact that the equilibrium formation of 6 was measured at two
different concentrations (Figures 3 and 4). The Keq was
calculated at both concentrations (using data from 2.5 equiv of
EtSO3H) assuming that 6 was either a solvent-separated ion
pair (Figure 3, Method 1) or an intimate ion pair (Figure 4,
The true background formation of 4 under “catalytic
conditions” was significantly slower than assumed on the
basis of the results shown in Figure 7c. In the time required for
complete consumption of 3 under catalytic conditions, only
8.6% of 4 is produced in the background reaction. Obviously,
this amount would be considerably less in the catalyzed
reaction because the concentration of 3 would be decreasing
faster (and the amount of phthalimide would be increasing
faster) as a result of the productive enantioselective pathway.
However, the formation of byproduct 5, which is not observed
in any of the catalytic reactions, suggests that this experiment is
still not perfectly mimicking the actual catalytic reaction
conditions.
DISCUSSION
■
1. Role of the Brønsted Acid. The irreproducibility of the
catalytic sulfenocarbocyclizations upon scale-up for descriptive
purposes revealed a dramatic sensitivity to the Brønsted acid
that was not seen in the preceding studies on sulfeno-
etherification reactions.2a Systematic reinvestigation of the
effects of Brønsted acid loading on the rate and selectivity of
the reactions, the formation of the catalytically active
sulfenylating agent, and the protonation equilibria for 2 was
highly informative and revealed a dramatic sensitivity of the
reaction behavior to the stoichiometry of the acid and also
overall concentration.
1.1. Comparison of Methane- and Ethanesulfonic Acids.
The Brønsted acidity of sulfonic acids has been the subject of
intense study for many years.7 Alkylsulfonic acids are classified
as “moderately strong acids”, with pKa’s between +2 and −2,
and as such are amenable to a variety of acidity determinations.
In water, methanesulfonic acid has pKa = −1.92, whereas that of
ethanesulfonic acid is −1.68. Similarly small differences have
been found in DMSO and acetonitrile. The slightly weaker
acidity of EtSO3H has been manifested in all of the experiments
described above: both catalyzed and uncatalyzed cyclizations of
3 proceed more slowly with EtSO3H than with MsOH.8 The
preparative advantage of EtSO3H that was used for all
descriptive cyclizations arises from the slightly larger difference
in the catalyzed and uncatalyzed reactions at lower loadings and
also the lower melting point that allowed cold delivery of the
acid.
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Method 2). Interestingly, the solution for the two concen-
trations using Method 1 produced two different Keq’s, whereas
the solution using Method 2 gave nearly identical Keq’s. From
these data, we assume that the catalytically active species is an
intimate ion pair in dichloromethane.
Scheme 2
1.4. Protonation Equilibria for N-Phenylsulfenylphthal-
imide. Sulfenylating agent 2 was shown to be significantly
protonated under standard reaction conditions (0.2 M, 1.00
equiv of RSO3H). The high rate of the uncatalyzed reaction (in
the absence of (S)-1) can be ascribed to the reactivity and
than that for PhSO3H or TsOH because of its weaker acidity
and corresponding greater basicity of MsO−, thus leading to a
higher concentration of the triple ion. In the cyclization
reactions, the base (B) is N-phenylthiophthalimide (2). With
1.00 equiv of EtSO3H, 2 is ca. 25% protonated, leading to a
significant concentration of the triple ion which sequesters two
additional molecules of EtSO3H.
concentration of 2·H+RSO3 . The greater difference in the rates
−
of the catalyzed and uncatalyzed reactions for EtSO3H
compared to MsOH can be understood from the differing
consequences of their acidities. The rates of the catalyzed
reactions are very similar because these reactions are governed
by the concentration of the active sulfenylating agent 6, which
reaches its (saturated) maximum in the presence of both acids
at 1.00 equiv loading. However, the weaker proton-donating
strength of EtSO3H compared to MsOH, as illustrated in the
measured Keq’s of protonation of 2, has a greater rate-
attenuating effect on the uncatalyzed reaction, thus leading to a
larger “split” in the catalyzed/uncatalyzed rates, which leads to a
better-behaved system for enantioselectivity.
An important issue that could well impact the understanding
of this phenomenon is the actual structure of the ion pairs
involved in the various stages of the reaction. Although the
structure of the catalytically active species 6 could be
established as an intimate ion pair in CHCl3, the structures
of 2·H+RSO3 and protonated phthalimide could not be
−
established. Clearly, the buffering power (i.e., homoconjugation
strength) will depend on the structure of the ion such that the
more solvent-separated the ions, the greater their ability to bind
to their conjugate acids.12
The dramatic drop in the rate of the uncatalyzed reaction
upon the addition of n-Bu4N+OMs− and phthalimide together
with the attendant decrease in the amount of MsOH implies
3. Mechanistic Rationale and Catalytic Cycles. The
formation of (racemic) 4 at a rate greater than that of the
catalyzed reaction provided a compelling explanation for the
variability of the enantioselectivities in preparative reactions,
but also presented a conundrum: how can a catalytic reaction
outcompete a faster stoichiometric reaction and produce
enantiomerically enriched products?
that the concentration of 2·H+RSO3 must be substantially
−
lower under the condition of the catalytic reaction for reasons
described below.
2. Role of Sulfonate Ions in the Uncatalyzed
Cyclization: The Structure of Ion Pairs. The counter-
intuitive observation that the cyclization of 3 in the absence of
catalyst (“racemic background reaction”) proceeded with a rate
comparable to that of the catalyzed cyclization of 3 (which
afforded high enantioselectivity) demanded a reevaluation of
the actual racemic background reaction that may intervene
under catalytic conditions. As shown in Figures 6 and 7,
sulfonate ions and phthalimide (necessary consequences of the
formation of the catalytically active species 6) were effective
inhibitors of the racemic background reaction. The results
shown in Figure 7c were most informative. With as little as 0.1
equiv of n-Bu4N+OMs−, 0.1 equiv of phthalimide, and 0.9 equiv
of MsOH (the actual stoichiometries with respect to 3 at the
beginning of the catalyzed reaction), the cyclization is
extremely slow, reaching less than 10% conversion in the
same time that the catalytic reaction would be complete. Thus,
the apparent contradiction seen in Figures 1 and 2 is, in reality, a
consequence of the incorrect assumption that the racemic
background reaction is accurately represented by simply leaving
out the catalyst.
A possible explanation for the inhibition of the racemic
background reaction under catalytic conditions may be found in
the buffering effect of the sulfonate ion. The strong buffering
effect of sulfonate ions on the acidity of sulfonic acids has in
fact been studied in nonaqueous media, but not in chlorinated
solvents. The self-association of acids with their conjugate
bases, known as the “homoconjugation reaction”, has been
studied for sulfonic acids in dipolar aprotic solvents.11a In the
conductometric titration of MsOH in benzonitrile (with Et3N),
a large maximum is observed at one-third of the equivalence
point. Such maxima are characteristic of the formation of triple
ions11b according to the formula shown in Scheme 2. The
maximum at one-third equivalence for MsOH is much larger
The answer to this question has been found in a deeper
understanding of the stoichiometry for generation of the
catalytically active sulfenylating agent 6 and in the buffering
effect of sulfonate ions and phthalimide formed under catalytic
conditions. These phenomena result in the simultaneous
operation of two catalytic cycles illustrated in Scheme 3.
Initiation of both cycles begins with the pre-equilibrium
protonation of 2 to form species i. Under catalytic conditions
(i.e., with 0.1 equiv of (S)-1) the catalyst is saturated as the
kinetically active sulfenylating agent 6 with as little as 0.4 equiv
of EtSO3H (with respect to 2). Once 6 is stoichiometrically
generated, the catalytic cycle has no further need for EtSO3H
(as was seen in the similarity of rates in Figure 2a). Any
additional acid would be deleterious in promoting the
uncatalyzed pathway, but the presence of MsO− from both i
and 6 serves to neutralize the excess acid and inhibit the
racemic background reaction. First-order kinetic behavior
requires that the formation of episulfonium ion iv be the
rate-determining step which is followed by rapid cyclization and
rearomatization.
The striking behavior of this catalytic system bears some
resemblance to the inhibition of the asymmetric catalytic
pathway in the Povarov reaction elegantly analyzed by
Jacobsen.13 In that study a similar observation was made
regarding the suppression of a Brønsted acid catalyzed racemic
background reaction that they ascribed to “negative catalysis”.14
The high association constant of the chiral urea for the
protonated imine resulted in the removal of the Brønsted acid
from the reaction. In our system, this behavior is reflected in
the formation of species 6. However, Jacobsen et al. employed
only half as much Brønsted acid as catalyst loading, whereas in
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Scheme 3
Scheme 4
our system the Brønsted acid is deployed in stoichiometric
quantities with respect to substrate. Thus, consuming 0.1 equiv
of EtSO3H in the formation of 6 is insufficient to explain the
inhibition of the background reaction. Instead, we have
reactions revealed a consistently high mass balance (>98%)
consisting of only 2, 3, and 4.
An alternative explanation for zeroth-order behavior would
be a rate-determining step outside of the catalytic cycle. If the
protonated sulfenylating agent i existed in an aggregated state
(perhaps intermolecularly hydrogen bonded) which had to
dissociate to form a catalytically competent agent, and all
downstream reactions were faster than dissociation, overall
zeroth-order behavior would be observed (Scheme 4). The
amount of reactive monomer would be dependent on the
amount of i, which is dependent only on the amount of
Brønsted acid. In the presence of (S)-1, either the monomer is
rapidly intercepted to form 6 or the catalyst is capable of
reacting with the aggregate in a rapid pre-equilibrium which (as
was established above) is acid dependent.15
−
identified the crucial role of the conjugate base EtSO3 in
sequestering the excess Brønsted acid through the homo-
conjugation reaction, which forms triple ions, as well as the
buffering effect of the phthalimide generated from 2.
Although not directly relevant to the focus of this study, the
curious zeroth-order dependence for the formation of 4 in the
absence of (S)-1 warrants comment (Figures 1b and 2b). This
unusual behavior implies that the rate of cyclization depends
only on the Brønsted acid, whose concentration does not
change over the course of the reaction (Scheme 3). This unique
dependence would obtain if the cyclization becomes rate
determining in the absence of the Lewis base catalyst. In this
scenario, the resting state is the species ii, whose concentration
is set by the amount of Brønsted acid employed. Since this step
is an intramolecular reaction, it will exhibit zeroth-order kinetic
dependence on 2 and 3. The subsequent rearomatization step
from iii should be very fast. This hypothesis posits that
intermediate ii should be observable under the reaction
conditions. However, NMR analysis of the uncatalyzed
CONCLUSION
■
Detailed kinetic and spectroscopic analysis of the enantio-
selective Lewis base/Brønsted acid co-catalyzed carbosulfenyl-
ation reaction has revealed a number of interesting features that
explain previously observed, contradictory behavior. The
unusual observation that the rate of the catalyzed reaction is
similar to that of the uncatalyzed process, yet still affords high
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(9) The different overall reaction order makes comparison of the
relative rates difficult. Under these conditions the times to 50%
conversions are calculated to be 2.0 h for the catalyzed reaction and
1.67 h for the uncatalyzed reaction.
(10) The initial rates of the catalyzed reactions are actually greater
than those of the uncatalyzed runs at comparable EtSO3H loadings,
but the differences in overall reaction order make comparisons
difficult. For example, the time to 50% conversion using 1.0 equiv of
EtSO3H is calculated to be 2.4 h for the catalyzed reaction and 7.1 h
for the uncatalyzed reaction.
enantioselectivity, is now understood. The actual background
reaction operating under catalytic conditions is not accurately
mimicked by simply leaving out the catalyst. In the presence of
the Lewis base catalyst, the active sulfenylating agent 6 is
formed quantitatively. Two byproducts of this step conspire to
inhibit the Brønsted acid catalyzed pathway, namely, equimolar
amounts of a sulfonate and phthalimide. The sulfonate forms
triple ions with the remaining sulfonic acid, thus sequestering
twice its molar concentration, and the phthalimide serves as a
buffer to neutralize additional amounts of the acid. The
consequences of these observations on other Brønsted acid
catalyzed reactions are currently under investigation.
(11) (a) Hojo, M.; Chen, Z. Anal. Sci. 1999, 15, 303−306. (b) Hojo,
M.; Hasegawa, H.; Miyauchi, Y.; Moriyama, H.; Yoneda, H.; Arisawa,
S. Electrochim. Acta 1994, 39, 629−638.
(12) Szwarc, M. In Ions and Ion Pairs in Organic Reactions; Szwarc,
M., Ed.; Wiley-Interscience: New York, 1972; Vol. 1, Chapt. 1.
(13) (a) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N.
Science 2010, 327, 986−990. (b) Knowles, R. R.; Jacobsen, E. N. Proc.
Natl. Acad. Sci. U.S.A. 2010, 107, 20678−20685.
ASSOCIATED CONTENT
■
S
* Supporting Information
All kinetic and spectroscopic data, along with preparation and
characterization of 5. This material is available free of charge via
the Internet at http://pubs.acs.org.
́
(14) (a) Retey, J. Angew. Chem., lnt. Ed. Engl. 1990, 29, 355−361.
(b) Breslow, R. Acc. Chem. Res. 1991, 24, 317−324. (c) Abel, E. Adv.
Catal. 1957, 9, 330−338.
(15) An intriguing consequence of this interpretation is that this
system may be operating analogously to the negative catalysis observed
by Jacobsen. If the amount of reactive monomer is small relative to the
amount of catalyst, then the interception of this highly reactive species
to form the less reactive, but chiral 6 could also explain these
observations. Studies on the colligative properties of i are underway.
AUTHOR INFORMATION
■
Corresponding Author
sdenmark@illinois.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Dr. Alex Jaunet is thanked for preliminary kinetic investigations.
We are grateful to the National Institutes of Health for
generous financial support (R01 GM85235).
REFERENCES
■
(1) (a) Denmark, S. E.; Jaunet, A. J. Org. Chem. 2014, 79, 140−171.
(b) Denmark, S. E.; Jaunet, A. J. Am. Chem. Soc. 2013, 135, 6419−
6422.
(2) (a) Denmark, S. E.; Kornfilt, D. J.-P.; Vogler, T. J. Am. Chem. Soc.
2011, 133, 15308−15311. (b) Denmark, S. E.; Kalyani, D.; Collins, W.
R. J. Am. Chem. Soc. 2010, 132, 15752−15765. (c) Denmark, S. E.;
Collins, W. R. Org. Lett. 2007, 9, 3801−3804.
(3) A parallel set of experiments run at 0.1 M concentration displayed
dramatically different behavior than those run at 0.2 M. For example,
with MsOH (1.0 equiv), the catalyzed reaction showed an induction
period of ca. 6 h before the rapid onset of reaction, approximating an
autocatalytic process. Moreover, with EtSO3H, the uncatalyzed
reaction afforded only 5, the product of proton-initiated cyclization.
These results, while intriguing and potentially informative, did not
represent the preparative-scale reactions and as such were not further
investigated or analyzed. See Supporting Information for details.
(4) The enantiomeric ratio (er) for 4 in this run using purified
MsOH was only 75:25.
(5) Enantiomeric ratios: 1.00 equiv, 86.9:13.1; 0.75 equiv, 90.2:9.8;
0.50 equiv, 92.6:7.4; 0.25 equiv, 92.9:7.1.
(6) It is recognized that the equilibria measured at −50 and −57 °C
may not be exactly the same as the equilibrium at the reaction
temperature (−20 °C); however, the temperature difference is not
large.
(7) For reviews, see: (a) King, J. F. In The chemistry of sulphonic acids,
esters and their derivatives; Patai, S., Rappoport, Z., Eds.; John Wiley &
Sons: Chichester, 1991; Chapt. 6. (b) Furukawa, N.; Fujihara, H. In
The chemistry of sulphonic acids, esters and their derivatives; Patai, S.,
Rappoport, Z., Eds.; John Wiley & Sons: Chichester, 1991; Chapt. 7.
(8) Only at 0.1 M concentration were the differences more
pronounced. EtSO3H did not promote the formation of 4 in the
uncatalyzed reaction but afforded only 5 in a process that exhibited
zeroth-order kinetic behavior. See Supporting Information for details.
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