Quantification of electrophilic activation by hydrogen-bonding organocatalysts

Article abstract of DOI:10.1021/ja5086244

A spectrophotometric sensor is described that provides a useful assessment of the LUMO-lowering provided by catalysts in Diels-Alder and Friedel-Crafts reactions. A broad range of 33 hydrogen-bonding catalysts was assessed with the sensor, and the relative rates in the above reactions spanned 5 orders of magnitude as determined via ¹H- and ²H NMR spectroscopic measurements, respectively. The differences between the maximum wavelength shift of the sensor with and without catalyst (Δλ_max^-1) were found to correlate linearly with ln(k_rel) values for both reactions, even though the substrate feature that interacts with the catalyst differs significantly (ketone vs nitro). The sensor provides an assessment of both the inherent reactivity of a catalyst architecture as well as the sensitivity of the reaction to changes within an architecture. In contrast, catalyst pK_a values are a poor measure of reactivity, although correlations have been identified within catalyst classes.

Full text of DOI:10.1021/ja5086244

Article
pubs.acs.org/JACS
Quantification of Electrophilic Activation by Hydrogen-Bonding
Organocatalysts
Ryan R. Walvoord, Phuong N. H. Huynh, and Marisa C. Kozlowski*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United
States
S
* Supporting Information
ABSTRACT: A spectrophotometric sensor is described that
provides a useful assessment of the LUMO-lowering provided by
catalysts in Diels−Alder and Friedel−Crafts reactions. A broad range
of 33 hydrogen-bonding catalysts was assessed with the sensor, and
the relative rates in the above reactions spanned 5 orders of
magnitude as determined via 1H- and 2H NMR spectroscopic
measurements, respectively. The differences between the maximum
−1
wavelength shift of the sensor with and without catalyst (Δλmax
)
were found to correlate linearly with ln(krel) values for both reactions,
even though the substrate feature that interacts with the catalyst
differs significantly (ketone vs nitro). The sensor provides an
assessment of both the inherent reactivity of a catalyst architecture as well as the sensitivity of the reaction to changes within an
architecture. In contrast, catalyst pKa values are a poor measure of reactivity, although correlations have been identified within
catalyst classes.
Scheme 1. UV−Vis Sensor Concept To Detect Weak
Interaction
1. INTRODUCTION
The field of small-molecule organocatalysis via noncovalent
interactions has seen rampant growth over the past decade.1
This area, which aims to mimic the mechanisms used by nature
in enzyme catalysis, is attractive due to its potential for high
catalyst tunability and substrate specificity, as well as obviating
the use of metals. While such research has resulted in many
catalysts operating through bifunctional mechanisms,2 the
primary interaction responsible for electrophile activation
occurs through hydrogen-bonding to an acceptor moiety. The
consequent LUMO-lowering results in rate enhancement. In
comparison to metal-based systems (i.e., Lewis Acids),3−5
current metrics to estimate the reactivity of hydrogen bonding
catalysts are ineffective. Although ΔpKa values of the donor and
acceptor may be used to infer hydrogen-bond strengths,6 this
analysis fails to account for several important secondary
interactions, including sterics, dual-activation, and binding
geometry.7 As a result, the discovery of reactions compatible
with hydrogen-bond catalysis is far outpacing understanding of
catalyst interaction and mechanism. Indeed, while certain
privileged organocatalyst motifs have been identified to be
successful for several reaction types, rational design of these
structures remains limited, relying on trial and error to achieve
optimal reactivity and selectivity.
organocatalysts, including several widely used motifs, with the
goal of encompassing many different hydrogen-bonding arrays.
An additional goal was to validate the sensor measurements
across significantly different reaction profiles, particularly those
involving noncarbonyl electrophiles. The lack of comprehensive
rate data for a range of catalysts in different reactions is a barrier
to understanding the factors controlling catalytic activation. As
a consequence, the relative rates have been measured for an
array of catalysts in two reactions with different groups that
interact with the catalysts. The sensor signal has been analyzed
with respect to reaction profile, catalyst structure, acidity, and
acceptor preference. Our findings establish the sensor as a
useful substrate “surrogate” for probing and gauging catalyst
In a previous communication,8 we described preliminary
results showing the utility of small organic chromophore S for
the detection of hydrogen-bonding interactions by UV−vis
spectroscopy for a small set of catalysts (Scheme 1). Herein, we
assess the general utility of this colorimetric sensor as a
predictive gauge for the relative reactivity of a broad range of
Received: August 21, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja5086244 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
performance. Moreover, the data unequivocally establish that
catalyst structure and binding mode are far more relevant to
catalytic activity than acidity.
hypsochromic shift in Figure 1. An increased shift (lower λmax)
is predicted for binders of ostensibly greater strength (e.g.,
proton > benzoic acid > phenol).
The UV absorption behavior of the sensor with the
hydrogen-bonding agent can be represented as shown in
Figure 2a. The lowest energy electronic transition may be
ascribed to the n (HOMO) to π* (LUMO) transition, ΔE1,
corresponding to the measured λmax. As supported by the above
calculations, addition of a hydrogen-bonding agent stabilizes
the ground state (HOMO) to a greater extent than the excited
state (LUMO), i.e., ΔE3 > ΔE2. As a consequence, a
hypsochromic shift is observed upon interaction of the sensor
with the hydrogen-bond donors. For comparison, Figure 2b
illustrates the energy diagram for a typical reaction with a
hydrogen-bonding catalyst, in which catalysis is effected by
LUMO-lowering of the electrophile (ΔEa). We hypothesized
that ΔE3 − ΔE2 is proportional to ΔEa, i.e., the wavelength shift
of the bound sensor•catalyst is proportional to the rate
enhancement afforded in a reaction with the hydrogen-bonding
catalyst.
2. RESULTS AND DISCUSSION
2.1. Application of a Colorimetric Probe for Determin-
ing LUMO Activation. A key consideration in designing a
method for measuring hydrogen-bond strengths is the very
broad range of these noncovalent interactions (0.2−40 kcal/
mol).9 Observing the very weak range of these interactions is a
challenge with commonly employed spectroscopic techniques.
For example, despite successful application in measuring Lewis
Acid binding effects,10 preliminary NMR studies proved too
insensitive for detecting the interactions of weak hydrogen-
bonding catalysts with a carbonyl acceptor.11
We proposed an alternative approach using the sensitivity of
UV−vis absorption profiles, in which a change in electronic
excitation of an acceptor chromophore occurs upon binding to
a hydrogen-bond donor (Scheme 1). Specifically, imidazopyr-
azinone S displays solvatochromism with protic solvents as well
as color changes with a small number of Lewis Acids.12 We
postulated that upon treatment with various hydrogen-bond
donors, the carbonyl moiety of S would act as an acceptor
moiety. The resulting hydrogen-bonding interaction would
alter the electronic transition of the chromophore, detectable
by simple UV−vis spectroscopy.
2.2. Correlation of Binding with Sensor Wavelength
Shift. As shown in Figure 1, a continuous wavelength shift was
revealed upon saturation of the sensor with the catalyst. The
lack of two distinct peaks in intermediate measurements
containing both bound and unbound sensor indicates a rapid
equilibration. Thus, plots of absorbance vs [catalyst] (see
Figure 3 for an example with bisamidinium 12) were used to
determine the binding constants (Keq) for the sensor•catalyst
complex. A significant range of blue shifts was observed for the
different catalyst donors, ranging from ∼490 to 465 nm (Δλmax
In line with this reasoning, treatment of sensor S in
dichloromethane with various hydrogen-bond donors resulted
in visible hypsochromic (blue) shifts (Figure 1). Importantly,
∼10−30 nm). In general, catalysts with larger Δλ
values
max
possessed much stronger binding constants. Since ΔE1 is
proportional to 1/λmax, the energetics of the interaction of the
sensor with the catalysts (ΔE3 − ΔE2) is proportional to 1/
λmax(sensor•catalyst) − 1/λmax(sensor). Indeed, a good
correlation of this inverse wavelength shift with ln(Keq) was
found (Figure 4). Note that in this plot, both axes are linearly
proportional to energy terms: Δλ−1 to the ΔE of the sensor
electronic absorption, and ln(Keq) to ΔG of sensor•catalyst
formation. Importantly, this relationship establishes the
observed wavelength shift as a reliable gauge for binding
affinity of a catalyst to the sensor molecule.
Using the sensor•catalyst wavelength shift as predictors of
catalyst reactivity yields several noteworthy observations. Diol-
based 30 (TADDOL) and silanol catalysts 31 and 32 afforded
very weak shifts, despite application in numerous trans-
formations, including Rawal’s seminal report on the asymmetric
hetero Diels−Alder reaction.14 The greater λmax shift of 32
compared to the related monosilanol 31 mirrors the increased
reactivity of this silanediol scaffold, as elegantly reported by
Mattson15 and Franz.16,17 Benzoic acids and phenols spanned
the intermediate range of sensor shifts, with trends clearly based
on the electronic effects of aromatic substitution. Although
these structures are not as commonly incorporated as
hydrogen-bond catalysts, Schafmeister and co-workers have
recently demonstrated the spiroligozyme catalyst 24, containing
a carefully arranged carboxylic acid and phenol, as an effective
ketosteroid isomerase mimic for the aromatic Claisen
rearrangement.18 N,N′-Diaryl thioureas and ureas, particularly
those with multiple trifluoromethyl substituents such as
Schreiner’s catalyst 4,19 afforded some of the largest sensor
shifts, indicative of the immense utility of these structures in
various organocatalysts.20 The internally activated BF2-urea 9
Figure 1. Response in the UV−vis spectrum of S upon increasing
amounts of 12. [S] = 2.22 × 10−5 M in CH2Cl2, [12] = 0 to 1.78 ×
10−4 M.
compounds anticipated to be weaker donors, such as
diphenylthiourea (1), yielded significant changes in sensor
signal. Variation of binder concentration resulted in titration-
like behavior, with a measurable end point upon saturation of
sensor with catalyst. An array of catalysts (Chart 1), varying in
structure and anticipated strength, was examined with the
colorimetric sensor, and the Δλmax upon saturation was
determined.
DFT molecular orbital calculations were performed on
bound and unbound sensor for selected hydrogen-bonding
agents to gauge the orbital perturbation (Table 1). The
calculated lowest energy transition accurately predicts the
observed absorbance maximum for the free sensor. More
importantly, the HOMO−LUMO energy gap was larger for all
bound complexes, in accord with the empirically observed
B
dx.doi.org/10.1021/ja5086244 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Chart 1. Hydrogen-Bonding Catalyst Structures Investigated
Table 1. Calculated HOMO−LUMO Energies for Bound
a
and Unbound Sensor Complexes
HOMO
(eV)
LUMO
(eV)
HOMO−LUMO
Calculated λmax
binder
(eV)
(nm)
-
−4.23
−5.11
−5.08
−9.43
−1.68
−2.18
−2.02
−6.08
2.55
2.92
3.05
3.35
487
425
407
370
phenol
PhCO2H
proton
a
Energies obtained from B3LYP/6-31G(d) optimized structures.
Figure 3. UV-titration curve of catalyst 12 in CH2Cl2 using [S] = 2.22
× 10−5 M. Inlay: visible color change of sensor before (red) and after
addition of 12 (yellow; [12] = 1.78 × 10−4 M).
solubility, and are typically employed as heterogeneous
catalysts. Representative squaramide 11, containing the
common N-3,5-(CF3)2aryl and N′-alkyl array, was synthesized,
and gave an apparent sensor end point of ∼480 nm. Due to its
relative insolubility, an accurate binding equilibrium value could
not be determined.
Figure 2. (a) Proposed energy diagram of the lowest energy electronic
transition of the sensor upon interaction with catalysts of increasing
strength, corresponding to the hypsochromic wavelength shift
(Δλmax). (b) LUMO-lowering of reactants via hydrogen-bonding
catalysts, corresponding to increased reaction rates (krel).
It is worth noting the experimental ease with which the
sensor metric can be obtained. Compound S itself is easily
obtained in 2 steps from commercial materials,12a,26 and very
little sensor or catalyst (particularly for strong catalysts) is
necessary to obtain the wavelength shift. The titration
experiment is largely insensitive to moisture, as illustrated by
the poor binding observed in the sensor titration with water.
Applying the method of continuous variation to the sensor
with catalyst 12 revealed a 1:1 binding stoichiometry with the
sensor molecule (Figure 5).13 This observation is significant,
since several other binding situations may be postulated,
including donation of one catalyst molecule to several sensors
(4 equivalent N−H bonds on 12, for example).
provided the largest shift within this class, in line with
experimental reactivity data reported by Mattson and co-
workers.21 Finally, formally cationic species, including guanidi-
nium, amidinium, and Takenaka’s azaindolium 1422 were the
strongest binders, with wavelength shifts ranging from 26 to 34
nm (λmax = 473−465 nm). Interestingly, one of the strongest
noncationic binders was thiophosphoramide 16, possessing a
pocket of three potential N−H donors. To date, this array has
seen only limited use in organocatalysis.23,24 Squaramide-
containing scaffolds have yielded excellent results as hydrogen-
bond activators;2a,25 however, these compounds possess limited
Benzoic acids and phenols offer useful templates to study
electronic effects on sensor signal due to availability and well-
C
dx.doi.org/10.1021/ja5086244 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 4. Correlation between sensor wavelength shift and sensor•catalyst binding equilibrium constant. All titrations were performed with [S] =
2.22 × 10−5 M in CH2Cl2.13
hypsochromic shifts of the sensor•catalyst complex. For both
catalyst sets, highly linear relationships are evident with
substituent σ parameters indicating that the wavelength shift
provides an accurate readout of electronic perturbation on the
hydrogen-bonding ability.
Notably, the wavelength shifts seen with the sensor do not
correspond directly with pKa either in water (Figure 7a, R2 =
0.0007) or DMSO (Figure 7b, R2 = 0.0950). However,
Figure 5. Job plot analysis of catalyst 12 with sensor S showing 1:1
binding stoichiometry.
understood behavior of aromatic substitution. Due to solubility
limitations, ortho-substituted benzoic acids were studied rather
than the para-substituted analogs. The electronic effects from
substitution on the sensor interaction can be illustrated via a
Hammett-type plot, as shown in Figure 6. As may be
anticipated from the Brønsted catalysis law (see Section 2.6
for further discussion), increasingly electron-withdrawing
substituents on these structures correlate with larger
Figure 7. Plot of catalyst acidity in water (a) or DMSO (b) vs
Figure 6. Correlation of Hammett σ parameters for o-benzoic acids
sensor•catalyst wavelength shifts. Correlation is only observed within
closely related catalyst groups.
27 and p-phenols (σpara) with sensor•catalyst wavelength shifts.
i
(σortho
)
D
dx.doi.org/10.1021/ja5086244 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
correlations are observed for closely related catalyst structures,
wherein electronic perturbations modify the acidity of the
donor moiety without introducing significant secondary effects.
This observation provides potential for the sensor to estimate
pKa values within a series of related compounds. Persubstituted
phenol 29 deviates from other phenolic catalysts, which may be
attributed to the increased steric demand around the donating
O−H bond.
The correlation of the observed blue shift with the binding
strength across a large range of hydrogen-bond donors proved
the metric to be able to quantitatively detect these interactions.
However, this finding does not necessitate a correlation with
catalyst reactivity. In order for this correlation to occur, the
sensor must be a good facsimile of the substrate that is
undergoing reaction. Other factors, including alternate binding
modes and steric effects, might come into play when a substrate
interacts with hydrogen-bonding agent in a catalyzed reaction.
2.3. Comparison of Sensor Shifts with Hydrogen-
Bond Catalyzed Diels−Alder Rate Data. To be a useful
metric for the community, the sensor signal must correlate to
empirically obtained rate enhancement via hydrogen-bond
catalysis (Scheme 2). Myriad reaction profiles have been
in triplicate. Relative rate constants, krel, were calculated as
described in eq 1 from the observed pseudo-first order rate
constant k′obs and background rate kbackground, and were
normalized for catalyst concentration N. The resulting values
directly provide the rate enhancement afforded by the catalyst.
⎛
⎝
⎞
⎠
k′obs − kbackground
⎜
⎜
⎟
⎟
krel
=
N
kbackground
(1)
As displayed in Figure 8, a plot of ln(krel) against the inverse
sensor wavelength shift of 18 catalysts shows an excellent
Scheme 2. Sensor as a Surrogate for an Electrophilic
Substrate
Figure 8. Correlation between the sensor•catalyst wavelength shift
and catalyst rate enhancement in the Diels−Alder reaction between
MVK and Cp.
correlation. Catalysts with greater blue shifts when treated with
the sensor show greater activity in the Diels−Alder reaction via
correspondingly greater LUMO lowering of the ketone in the
dienophile. More precisely, the change in energy of the sensor
upon binding with the catalyst is proportional to the change in
activation energy of the hydrogen-bond catalyzed Diels−Alder
reaction.
The observed correlation establishes that, at least in this class
of reaction, the sensor signal is a good indicator of LUMO-
lowering ability of these small molecules as hydrogen-bond
catalysts. Importantly, the results also indicate that the binding
interaction of the sensor with catalysts is similar to that of
methyl vinyl ketone with catalyst, i.e. the sensor is a useful
gauge of carbonyl activation.
2.4. Comparison of Sensor Shifts with Hydrogen-
Bond Catalyzed Friedel−Crafts Rate Data. The addition of
various nucleophiles into nitroalkenes is one of the most widely
used reaction motifs in hydrogen-bonding catalysts; it is often
used as a measure of reactivity when developing and comparing
novel catalyst structures.7d,15a,16,21a,22,28 To test the effective-
ness of our sensor metric beyond the Diels−Alder reaction, we
studied the Friedel−Crafts addition of N-methylindole (34)
into nitrostyrene 35 (Scheme 4). Deuterated 35 was easily
prepared via Henry condensation using d3-nitromethane with
the corresponding aldehyde. Again, the number of hydrogen
reported that are established to proceed via hydrogen-bond
activation of the electrophile (LUMO-lowering activation). In
order to best isolate the reactivity enhancement offered by the
catalysts strictly due to hydrogen-bonding, we first targeted a
reaction where the electrophile has only one possible point of
interaction with the catalyst, and the nucleophile does not
contain binding points (i.e., no heteroatoms). Additionally, the
reaction should have minimal background rate and a method to
easily analyze starting material and/or product concentrations.
The reaction of methyl vinyl ketone (MVK) with cyclo-
pentadiene (Cp) offers a useful reaction platform that fulfills
these criteria (Scheme 3), and has been used to gauge the
1
Scheme 3. Diels−Alder Kinetic Study via H NMR
relative strength of thiourea19a and bisphenol7b catalysts
previously. Hydrogen-bonding to the ketone carbonyl accounts
for catalysis in this reaction. Importantly, the binding in the
sensor•catalyst complex is very similar to that of the
MVK•catalyst intermediate as both interactions arise from a
carbonyl acting as a hydrogen-bond acceptor.
2
Scheme 4. Friedel−Crafts Kinetic Study via H NMR
Systematic investigation of the Diels−Alder reaction of MVK
and Cp with a variety of catalysts was performed under pseudo-
first order conditions as described in Scheme 3. Kinetic data
1
was acquired via continuous sampling (5 min intervals) by H
NMR spectroscopy, and each rate measurement was performed
E
dx.doi.org/10.1021/ja5086244 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
bond acceptors is limited in this reaction. Nucleophile 34
provides a reasonably active coupling partner while minimizing
potential catalyst interactions [pKa(H2O) N-methylindolium =
−1.8].29 Thus, the effects of hydrogen bonding catalysts on the
activation of the styrene electrophile via binding to the nitro
acceptor can be cleanly delineated.
Significantly, the catalyzed rates of this reaction allow
comparison of the effects of hydrogen-bonding catalysts on
carbonyl acceptors (the sensor and MVK) versus nitro
acceptors (nitrostyrene 35) as outlined in Scheme 5. While
employment of a deuterium label provides exceptional signal
isolation. Moreover, overlap of signals from the catalyst is
completely mitigated, since only substrate, product, and
internal standard exhibit appreciable resonances. As a result,
any catalyst can be readily analyzed.
The Friedel−Crafts reaction was studied under pseudo-first
order conditions using the broad series of hydrogen-bond
catalysts shown in Chart 1. The relative catalytic strength of
each catalyst was calculated according to eq 1, using averaged
k′obs values from duplicate trials. A plot of ln(krel) and inverse
sensor wavelength shift is shown in Figure 10a. Similar to the
Scheme 5. Catalyst−Acceptor Binding for Sensor and
Reaction Electrophiles
binding geometries to carbonyl groups are anticipated to be
similar, an analogous correlation may not be automatically
presumed for a nitro group. In particular, the nitro group
contains a formally delocalized negative charge across three
atoms, and has been suggested to form κ2-activated
intermediates with certain catalyst structural types such as
squaramides and thioureas.21b,f,30
As illustrated in Figure 9, kinetic reaction data was acquired
using 2H NMR spectroscopy. Although initial 1H NMR
spectroscopic studies with proteo-35 provided usable data,
Figure 10. (a) Correlation observed between the sensor•catalyst
wavelength shift and catalyst rate enhancement in the Friedel−Crafts
reaction. (b) Correlations based on catalyst structure groups.
Diels−Alder reaction, and predicted based on sensor shifts,
cationic binders proved to be the most effective catalysts,
followed by electron-deficient ureas and thioureas. Squaramide
11, employed here as a heterogeneous catalyst, provided
moderate rate enhancement as predicted by its sensor
wavelength shift. Thiophosphoramide 16 and sulfonamide 6
have previously been studied in a Friedel−Crafts reaction under
nearly identical conditions by Shea and co-workers.23a The krel
values reported for these catalysts and 4 align closely with the
values measured in this work.
The overall correlation of the sensor wavelength shift with
catalyst strength for the Friedel−Crafts reaction is good (R2 =
0.84), but not as strong as that found in the Diels−Alder
reaction (R2 = 0.95). Analysis of this data suggests that the
binding interaction of a hydrogen-bonding catalyst with the
sensor carbonyl does not fully mimic that of a hydrogen-
bonding catalyst with the activated nitroalkene. Closer
inspection reveals that the wavelength shift is correlated even
more strongly to catalyst strength within an isostructural catalyst
series (Figure 10b). Specifically, the catalysts can be placed in
four groups based on their general structure: benzoic acids,
phenols, “Y-type” binders, and other N−H binders. The Y-type
2
Figure 9. (a) Stacked H NMR plot and (b) kinetic profile for the
Friedel−Crafts reaction shown in Scheme 4 using catalyst 12.
Conditions: [34] = 1.33 M, [35] = 0.133 M, [37] = 0.133 M, [12]
= 2.67 × 10−4 M. The CDCl3 peak arises from natural abundance in
CHCl3.
F
dx.doi.org/10.1021/ja5086244 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
group consists of catalysts possessing two N−H donor groups
separated by a single atom, such as ureas, thioureas, guanidines,
bis-sulfonamides, etc. The other N−H binders include those
catalysts that have more than one atom separating the donor
array (squaramide 11, bisamidinium 12) or can only donate
one N−H bond (benzotriazole 15, monoamidinium 13).
Interestingly, the silanediol catalyst 32 exhibits reactivity falling
nicely in line with benzoic acids, possibly due to a similar O−H
geometry. This analysis quantitatively shows that Y-type
structures are superior for nitroalkene activation. In contrast,
phenols provided the least activation relative to their binding
interaction with the sensor.
Overall, the sensor provides a good assessment of relative
reactivity of hydrogen-bond catalysts in the Friedel−Crafts
reaction. The presence of stronger correlations within catalyst
structural classes is consistent with some catalysts activating
nitroalkenes via a different mode (e.g., κ2-binding) that is not
completely captured by the interactions of the catalysts with the
carbonyl of the sensor molecule. This analysis underlines the
complex nature of hydrogen-bonding, emphasizing that caution
must be exercised in generalizing catalyst reactivity or selectivity
from one reaction to another.
reaction. Accordingly, the slope and intercept data from Figure
10b were combined with the R and C values from Table 2 to
afford coefficient values for rFC and cFC, respectively, as
provided in Table 3.
ln(krel) = rrRrΔ(λ−1) + crCr
(3)
Table 3. Catalyst Structure Coefficients for Friedel−Crafts
Catalysis
catalyst series
Y-type
rFC
cFC
1.00
0.68
1.06
0.86
0.80
0.56
1.39
0.92
Benzoic Acids
Phenols
Other N−H Binders
The coefficient values in Table 3 reveal general trends
between the different catalyst structural types and rate in the
Friedel−Crafts reaction. Again, rFC values are a measure of
responsiveness of a given catalyst architecture to a perturbation
in sensor binding. For Y-type and phenolic catalysts, rFC is
noticeably higher than the other N−H binders, and particularly
benzoic acids. Thus, for the same amount of wavelength shift,
the phenol and Y-type catalysts provide greater increases in
reactivity relative to the other N−H binders and benzoic acids.
This observation indicates that the sensor can assess electronic
effects in a catalyst series. Comparison of the Hammett effects
on Δλ−1 (Figure 6; ρacid = 5.8, ρphenol = 4.4) with those on
ln(krel) (ρacid = 0.60, ρphenol = 0.33)13 provides support for this
assertion; both measures show a stronger electronic effect for
the carboxylic acid series.
On the other hand, lower cFC values indicate the inherent
complementarity of a given catalyst architecture. For example,
the Y-type binders activate nitro electrophiles to a greater
extent at a given wavelength shift relative to phenols or the
other N−H binders. Interestingly, the cFC value for benzoic
acids would predict high catalytic activity relative to Y-type
binders, but only in the weak binding regime (left side of plot).
Due to the low rFC value for benzoic acids, the trends invert
such that Y-type binders are superior in the strong binding
regime (right side of plot). Considering both terms together,
the Y-type binders are both more complementary to the
nitroalkene and more efficient at LUMO lowering, thereby
providing superior reactivity.
2.6. Comparison of Catalyst Reactivity and Acidity:
Brønsted Analysis. Acidity values have widely been used as a
guiding principle in hydrogen-bond catalyst design, under the
premise that a more acidic donor will form a stronger
interaction and stabilize the buildup of anionic charge in the
transition state to a greater extent. Indeed, several reports have
observed increased activity with judicious electronic tuning of
the donor hydrogen.17c,38 However, even ostensibly subtle
changes to catalyst structure can cause secondary factors to
override the reliability of pKa as a predictive measure, as
demonstrated by Cheng’s recent study39 on thiourea derivatives
and even noted in the seminal work by Hine on mono- and bis-
phenols.40 Having proved the effectiveness of the sensor signal
as a gauge for catalyst strength, we undertook a comparison
with acidity to determine the similarities and differences
between the two metrics.
2.5. Unified Description of Reactivity versus Sensor
Measurements. A general equation to describe catalyst
strength for reaction r based on sensor response (Δλ−1) is
presented in eq 2. Parameter Rr (slope) represents the
responsiveness of the rate per unit catalyst strength as
determined by the sensor measurement. Parameter Cr (y-
intercept) corresponds to inherent complementarity of the
catalyst to the electrophilic reaction partner.
Catalyst Reactivity ∝ ln(krel) = RrΔ(λ−1) + Cr
(2)
The parameter values (Table 2) for the reactions shown in
Scheme 3 (Diels−Alder) and Scheme 4 (Friedel−Crafts) were
Table 2. Reaction Coefficients for Equation 3
reaction
R
C
Diels−Alder
Friedel−Crafts
7.08
9.59
−6.36
−4.46
obtained using the kinetic data from Figures 8 and 10,
respectively. Comparison of the RDA and RFC values reveals that
the Friedel−Crafts is more sensitive to catalyst strength. In
other words, the same catalyst produces a greater relative rate
enhancement for the Friedel−Crafts reaction than for the
Diels−Alder reaction. Similarly, a given wavelength shift of the
sensor by a catalyst will cause a greater reactivity change in the
Friedel−Crafts vs the Diels−Alder reaction. On the other hand,
the CDA and CFC values indicate the inherent complementarity of
the electrophilic substrate with catalysts; greater complementar-
ity translates to greater reactivity. Notably, the C values
represent reactivity when there is no wavelength shift (no
perturbation of the sensor by the catalysts) and represent the
lower limit of LUMO activation afforded by the catalyst.
Catalyst group-specific coefficients rr and cr can be
introduced (eq 3) to account for variation if the sensor binds
the catalyst differently than the reaction electrophile. Due to
the strong correlation of the sensor shift to relative rates
independent of catalyst structure, coefficients are unnecessary
for the Diels−Alder reaction (rDA ≈ cDA ≈ 1). As discussed in
Section 2.4, the sensor does not completely model catalyst
binding to the nitrostyrene acceptor of the Friedel−Crafts
Aggregate data for all catalysts spanning 3 orders of
magnitude in reactivity for the Diels−Alder reaction and 4
orders in the Friedel−Crafts reaction is organized by increasing
G
dx.doi.org/10.1021/ja5086244 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Table 4. Sensor Shifts, Binding Constants, Relative Rate Data, and Acidity Values for Catalysts Investigated
catalyst
H2O (33)
λmax (nm)
Keq (M−1
)
krel (Diels−Alder)
krel (Friedel−Crafts)
pKa (H2O)
pKa (DMSO)
a
a
495.2
490.8
490.4
490.0
487.2
487.0
486.2
486.2
485.4
484.2
484.0
484.0
482.6
482.2
481.0
480.8
480.4
480.0
480.0
480.0
479.8
479.8
479.6
478.0
477.2
477.0
475.0
474.4
473.2
473.0
470.0
469.8
465.0
-
2.54
-
-
-
15.75
32
b
(R,R)-TADDOL (30)
TBDMSiOH (31)
Diphenylthiourea (1)
Silanediol (32)
1.57 × 101
4.87
0.023
-
∼16
∼12
28−30
c
-
-
d
1.67 × 101
7.88 × 101
3.18 × 101
4.30 × 101
7.04 × 101
8.35 × 101
6.57 × 101
1.50 × 102
1.07 × 102
2.15 × 102
1.04 × 103
6.05 × 102
4.92 × 102
1.05 × 103
-
0.012
-
0.68
1.82
0.35
0.25
3.21
1.72
2.12
0.93
7.13
5.81
36.4
4.94
2.82
24.1
12.5
-
-
13.4
c
11.8
-
e
e
,
f
(R)-BINOL (25)
4-t-Bu-phenol (26)
2-Me-BzOH (17)
BzOH (18)
0.034
-
10.28
17.1
g
a
10.23
∼18
11.07
g
h
h
-
3.91
g
0.086
-
4.20
11.00
g
a
Benzotriazole (15)
4-Br-phenol (27)
(CF3)2-thiourea (2)
2-Cl-BzOH (19)
Sulfonamide (5)
4-NO2-phenol (28)
F5-phenol (29)
8.38
11.9
g
0.224
0.049
-
9.34
-
d
-
10.7
g
h
2.94
9.70
a,i
0.337
0.733
-
-
<12.9
g
a
7.14
10.8
j
5.53
-
d
(CF3)2-urea (6)
0.724
-
-
16.1
k
l
Squaramide (11)
-
11.5−12.0
Spiroligozyme (24)
2-NO2−BzOH (20)
(CF3)3-thiourea (3)
(CF3)4-urea (8)
(CF3)3-urea (7)
3,5-NO2−BzOH (21)
F5−BzOH (22)
(CF3)4-thiourea (4)
Thiophosphoramide (16)
BF2-urea (9)
6.30 × 102
8.27 × 102
4.52 × 102
9.38 × 103
2.52 × 103
1.02 × 103
1.41 × 103
1.77 × 103
3.11 × 103
2.65 × 104
1.84 × 104
3.34 × 103
5.49 × 103
-
-
4−5
2.17
-
g
h
0.669
0.442
-
22.8
47.0
120.0
73.4
-
8.66
d
-
-
-
-
9.5
d
13.8
d
-
14.9
-
-
-
m
1.04
1.22
1.23
-
22.2
130.6
291.1
603.5
1446
89.1
-
1.75
d
-
-
-
8.5
-
n
7.5
g
o
Guanidinium (10)
MonoAmidinium (13)
TFA (23)
2.81
3.69
-
10.12
14
g
p
p
11−12
12.8−13.6
g
0.23
-
g
q
Azaindolium (14)
BisAmidinium (12)
PPTS
12.2
35.1
0.190
0.951
8.53
2604
2763
72.7
26.9
4.6
6
g
3.22 x105
11−12
12.8−13.6
a
a
-
5.2
3.4
g
Diphenylphosphate
CSA
-
-
1.29
-
a
a
-
e
-
103.3
−0.6
1.6
a
b
c
d
f
g
h
i
Ref 31. Ref 32. Ref 17c. Ref 41. Ref 33. Value for 2-naphthol. Ref 29. .Ref 27. Value for the less acidic N-phenylmethanesulfonamide
j
k
l
m
n
o
p
q
analogue. Ref 34. Titrations and reactions were performed heterogeneously. Ref 42. Ref 35. Ref 38c. Ref 36. Ref 37. Ref 22.
sensor wavelength shift in Table 4. Recent efforts by
Schreiner41 and others42 provided accurate acidity values of
common hydrogen-bond donors. The Brønsted catalysis
equation (eq 4), which describes the relationship for the rate
of an acid-catalyzed reaction with the pKa of the acid,43 was
applied to this data.
log(k) = α log(Ka) + b
(4)
Figures 11 and 12 display the results for selected catalyst
series in the Diels−Alder and Friedel−Crafts reactions,
respectively.44 These plots prove the linear free energy
relationships (LFERs)45 between catalyst acceleration and
acidity among catalysts of very similar structure. In general,
these LFERs exhibited a narrow range of α values (0.39−0.47;
Table 5), indicating a similar degree of hydrogen-bonding in
the transition states and that these reactions are not proceeding
through formal protonation (α = 1). Slightly higher values
found for benzoic acids in the Diels−Alder (α = 0.57) indicate
a greater degree of proton transfer in the transition states
consistent with the ionic nature of benzoic acids. Lower values
for ureas in the Friedel−Crafts (α = 0.31) indicate a lesser
Figure 11. Brønsted catalysis plot for the Diels−Alder reaction,
demonstrating LFERs for closely related catalyst groups.
degree of proton transfer in the transition states in line with the
covalent nature of the N−H bonds.
More significantly, these figures clearly demonstrate the
inherent limitations of estimating catalyst strength using acidity
metrics. A pertinent example can be found in the thiourea and
urea catalysts. Based solely on pKa measurements, thioureas
H
dx.doi.org/10.1021/ja5086244 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
3, which provides a direct means of assessing the reactivity of a
catalyst in a given reaction using the sensor signal. The
resulting parameters also reveal relationships between sub-
strate•catalyst binding, catalyst-induced LUMO-lowering, and
catalyst structure.
Investigation of additional catalyzed reactions with the
sensor, empirically or computationally, has the potential to
expand eq 3 to achieve quantitative predictive power across a
large range of reaction platforms and catalysts (hydrogen
bonding, Brønsted acid, and Lewis acid). Further studies to
achieve this goal are underway.
ASSOCIATED CONTENT
* Supporting Information
■
Figure 12. Brønsted catalysis plot for the Friedel−Crafts reaction
demonstrating LFERs for closely related catalyst groups.
S
Experimental procedures, characterization of new compounds,
UV-titration data, and Diels−Alder and Friedel−Crafts rate
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
Table 5. Brønsted α-Values for Different Catalyst Structural
Types from Figures 11 and 12
α
AUTHOR INFORMATION
Corresponding Author
marisa@sas.upenn.edu
catalyst series
solvent
Diels−Alder
Friedel−Crafts
■
Thioureas
Ureas
DMSO
DMSO
DMSO
H2O
0.41
-
0.47
0.31
0.39
0.46
0.39
Benzoic Acids
Benzoic Acids
Phenols
-
Notes
0.57
0.39
The authors declare no competing financial interest.
H2O
ACKNOWLEDGMENTS
■
would be predicted to provide much higher activity. In practice,
the opposite is observed where ureas exhibited greater (6, 7 vs
2, 3) or similar (8 vs 4) activation of the nitro group compared
to their thiourea analogues, despite the much greater acidity of
the thioureas (4−5 orders of magnitude difference). Highly
reactive catalysts not belonging to a clearly defined series,
including common Brønsted acids, are included in Figure 11
and further highlight the disparity between acidity and activity.
Interestingly, Takenaka’s azaindolium catalyst 14 displayed
much higher activity than PPTS, despite similar acidities and
similar pyridinium−H donor moieties. Taken together, these
observations reinforce the risks of using pKa measurements to
estimate reactivity.
We are grateful to NIH (GM-087605) for financial support of
this research. Partial instrumentation support was provided by
the NIH for MS (1S10RR023444) and NMR
(1S10RR022442). Thanks to Christian Schafmeister (Temple
University) for donations of catalyst 24 and to Anita Mattson
(Ohio State University) for 9 and 32. We are indebted to Drs.
George Furst and Jun Gu (UPenn) for NMR assistance. Dr.
Osvaldo Gutierrez and Sergei Tcyrulnikov (UPenn) are
acknowledged for helpful discussions. We thank Ms. Kaila
Orlandini for UV-titration experiments.
REFERENCES
■
(1) (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,
1520−1543. (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107,
5713−5743. (c) Akiyama, T. Chem. Rev. 2007, 107, 5744−5758.
(d) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289−296. (e) Akiyama,
T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999−1010.
(f) Connon, S. J. Synlett 2009, 354−376. (g) Takemoto, Y. Chem.
Pharm. Bull. 2010, 58, 593−601. (h) Sohtome, Y.; Nagasawa, K.
Synlett 2010, 1−22. (i) Schenker, S.; Zamfir, A.; Freund, M.;
Tsogoeva, S. B. Eur. J. Org. Chem. 2011, 2209−2222. (j) Auvil, T.
J.; Schafer, A. G.; Mattson, A. E. Eur. J. Org. Chem. 2014, 2633−2646.
(2) Select examples: (a) Aleman, J.; Parra, A.; Jiang, H.; Jørgensen, K.
A. Chem.Eur. J. 2011, 17, 6890−6899 and references therein.
(b) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672−12673. (c) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem.,
Int. Ed. 2005, 44, 4032−4035. (d) Herrera, R. P.; Sgarzani, V.;
Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 6576−579.
(e) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7,
1967−1969. (f) Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2007,
129, 15872−15883. (g) Connon, S. J. Chem. Commun. 2008, 2499−
2510.
3. CONCLUSIONS
In conclusion, a sensor is described that provides an assessment
of the reactivity over 3−4 orders of magnitude for 33 hydrogen-
bonding catalysts. Useful correlations are obtained between the
wavelength shifts that catalysts cause to the pyrazinone sensor
and the rate-determining steps in Diels−Alder and Friedel−
Crafts reactions. As a result, only the wavelength shifts upon
saturation of the sensor with catalysts need to be measured vs
the more time-consuming titration studies. Consequently, the
sensor may also find use as a rapid means for measuring pKa
values in series of related compounds.
In contrast to established acidity (pKa) values, the sensor
wavelength shift is a highly predictive metric for the relative
reactivity of catalysts encompassing a broad range of structures
and strengths. Notable acidity-activity disparities include
cationic catalysts (low acidity, high reactivity), and benzoic
acids (high acidity, low reactivity), the strengths of which are
more accurately gauged by their interaction with the sensor.
Overall, the sensor is a superior surrogate for the diverse
electrophiles (enone and nitroalkene) used compared to water
and is better able to assess secondary interactions. The data
collected was used to formulate the relationship described in eq
(3) Fukuzumi parameters: (a) Fukuzumi, S.; Ohkubo, K. Chem.
Eur. J. 2000, 6, 4532−4535. (b) Fukuzumi, S.; Ohkubo, K. J. Am.
Chem. Soc. 2002, 124, 10270−10271.
(4) Irving-Williams order: (a) Irving, H.; Williams, R. J. P. Nature
1948, 162, 746−747. (b) Irving, H.; Williams, R. J. P. J. Chem. Soc.
1953, 3192−3210.
I
dx.doi.org/10.1021/ja5086244 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(5) Breugst, M.; Gree, R.; Houk, K. N. J. Org. Chem. 2013, 78, 9892−
9897.
(6) Gilli, P.; Pretto, L.; Bertolasi, V.; Gilli, G. Acc. Chem. Res. 2009,
(23) (a) Rodriguez, A. A.; Yoo, H.; Ziller, J. W.; Shea, K. J.
Tetrahedron Lett. 2009, 50, 6830−6833. (b) Borovika, A.; Tang, P.-I.;
Klapman, S.; Nagorny, P. Angew. Chem., Int. Ed. 2013, 52, 13424−
13428. (c) Cranwell, P. B.; Hiscock, J. R.; Haynes, C. J. E.; Light, M.
E.; Wells, N. J.; Gale, P. A. Chem. Commun. 2013, 49, 874−879.
(24) The use of a chiral thiophosphorodiamide catalyst for an
asymmetric addition of naphthoquinones into β-nitrostyrenes has been
described: Wu, R.; Chang, X.; Lu, A.; Wang, Y.; Wu, G.; Song, H.;
Zhou, Z.; Tang, C. Chem. Commun. 2011, 47, 5034−5036.
(25) Select examples of squaramide-based organocatalysis: (a) Mal-
erich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130,
14416−14417. (b) Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem.,
Int. Ed. 2010, 49, 153−156. (c) Konishi, H.; Lam, T. Y.; Malerich, J.
P.; Rawal, V. H. Org. Lett. 2010, 12, 2028−2031. (d) Yang, W.; Du, D.-
M. Org. Lett. 2010, 12, 5450−5453. (e) Qian, Y.; Ma, G.; Lv, A.; Zhu,
H.-L.; Zhao, J.; Rawal, V. H. Chem. Commun. 2010, 46, 3004−3006.
(f) Yang, W.; Yang, Y.; Du, D.-M. Org. Lett. 2013, 15, 1190−1193.
(g) Manoni, F.; Connon, S. J. Angew. Chem., Int. Ed. 2014, 53, 2628−
2632.
42, 33−44.
(7) (a) Annamalai, V. R.; Linton, E. C.; Kozlowski, M. C. Org. Lett.
2009, 11, 621−624. (b) Tuerkmen, Y. E.; Rawal, V. H. J. Org. Chem.
2013, 78, 8340−8353. (c) Shokri, A.; Wang, Y.; O’Doherty, G. A.;
Wang, X.-B.; Kass, S. R. J. Am. Chem. Soc. 2013, 135, 17919−17924.
(d) Beletskiy, E. V.; Schmidt, J.; Wang, X.-B.; Kass, S. R. J. Am. Chem.
Soc. 2012, 134, 18534−18537.
(8) Huynh, P. N. H.; Walvoord, R. R.; Kozlowski, M. C. J. Am. Chem.
Soc. 2012, 134, 15621−15623.
(9) Steiner, T. Angew. Chem., Int. Ed. 2002, 41, 48−76.
(10) (a) Deters, J. F.; McCusker, P. A.; Pilger, R. C., Jr. J. Am. Chem.
Soc. 1968, 90, 4583−4585. (b) Hilt, G.; Puenner, F.; Moebus, J.;
Naseri, V.; Bohn, M. A. Eur. J. Org. Chem. 2011, 5962−5966 and
references therein.
(11) For a relevant example of monitoring hydrogen-bonding
interactions with stronger thiourea catalysts, see: Lippert, K. M.;
Hof, K.; Gerbig, D.; Ley, D.; Hausmann, H.; Guenther, S.; Schreiner,
P. R. Eur. J. Org. Chem. 2012, 5919−5927.
(12) (a) Nakai, S.; Yasui, M.; Nakazato, M.; Iwasaki, F.; Maki, S.;
Niwa, H.; Ohashi, M.; Hirano, T. Bull. Chem. Soc. Jpn. 2003, 76, 2361−
2387. (b) Sekiguchi, T.; Maki, S.; Niwa, H.; Ikeda, H.; Hirano, T.
Tetrahedron Lett. 2004, 45, 1065−1069. (c) Takamuki, Y.; Maki, S.;
Niwa, H.; Ikeda, H.; Hirano, T. Chem. Lett. 2004, 33, 1484−1485.
(d) Takamuki, Y.; Maki, S.; Niwa, H.; Ikeda, H.; Hirano, T.
Tetrahedron 2005, 61, 10073−10080. (e) Hirano, T.; Sekiguchi, T.;
Hashizume, D.; Ikeda, H.; Maki, S.; Niwa, H. Tetrahedron 2010, 66,
3842−3848.
(13) See Supporting Information for additional experimental details.
(14) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature
2003, 424, 146.
(15) (a) Schafer, A. G.; Wieting, J. M.; Mattson, A. E. Org. Lett. 2011,
13, 5228−5231. (b) Schafer, A. G.; Wieting, J. M.; Fisher, T. J.;
Mattson, A. E. Angew. Chem., Int. Ed. 2013, 52, 11321−11324.
(16) Tran, N. T.; Wilson, S. O.; Franz, A. K. Org. Lett. 2012, 14,
186−189.
(17) For additional reports investigating silanol and silanediol
catalysis see: (a) Kondo, S.-I.; Harada, T.; Tanaka, R.; Unno, M. Org.
Lett. 2006, 8, 4621−4624. (b) Tran, N. T.; Min, T.; Franz, A. K.
Chem.Eur. J. 2011, 17, 9897−9900. (c) Liu, M.; Tran, N. T.; Franz,
A. K.; Lee, J. K. J. Org. Chem. 2011, 76, 7186−7194. (d) Wilson, S. O.;
Tran, N. T.; Franz, A. K. Organometallics 2012, 31, 6715−6718.
(e) Min, T.; Fettinger, J. C.; Franz, A. K. ACS Catal. 2012, 2, 1661−
1666. (f) Beemelmanns, C.; Husmann, R.; Whelligan, D. K.;
Ozcubukcu, S.; Bolm, C. Eur. J. Org. Chem. 2012, 3373−3376.
(g) Tran, N. T.; Wilson, S. O.; Franz, A. K. Chem. Commun. 2014, 50,
3738−3740.
(18) Parker, M. F. L.; Osuna, S.; Bollot, G.; Vaddypally, S.; Zdilla, M.
J.; Houk, K. N.; Schafmeister, C. E. J. Am. Chem. Soc. 2014, 136,
3817−3827.
(19) (a) Wittkopp, A.; Schreiner, P. R. Chem.Eur. J. 2003, 9, 407−
414. (b) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289−296.
(20) (a) Connon, S. J. Chem.Eur. J. 2006, 12, 5418−5427.
(b) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299−4306. (c) Tan,
B.; Hernandez-Torres, G.; Barbas, C. F., III. J. Am. Chem. Soc. 2011,
133, 12354−12357.
(26) Barlin, G. B.; Brown, D. J.; Kadunc, Z.; Petric, A.; Stanovnik, B.;
Tisler, M. Aust. J. Chem. 1983, 36, 1215−1220.
i
(27) The parameter σo was used to account for ortho electronic
influences: Pytela, O.; Liska, J. Collect. Czech. Chem. Commun. 1994,
59, 2005−2021.
(28) (a) Shokri, A.; Wang, X.-B.; Kass, S. R. J. Am. Chem. Soc. 2013,
135, 9525−9530. (b) Fleming, E. M.; McCabe, T.; Connon, S. J.
Tetrahedron Lett. 2006, 47, 7037−7042. (c) Zhuang, W.; Hazell, R. G.;
Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 2566−2571.
(d) Lancianesi, S.; Palmieri, A.; Petrini, M. Chem. Rev. 2014, 114,
7108−7149 and references therein.
(29) Jencks, W. P.; Regenstein, J. Ionization Constants of Acids and
Bases. In CRC Handbook of Biochemistry and Molecular Biology, 3rd ed.;
Fassman, G. D., Ed.; CRC Press: Cleveland, OH, 1975; Vol. 1, pp
305−351.
(30) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170−
7171.
(31) Bordwell, F. G. Acc. Chem. Res. 1998, 21, 456−463.
(32) Belokon, Y. N.; Harutyunyan, S.; Vorontsov, E. V.; Peregudov,
A. S.; Chrustalev, V. N.; Kochetkov, K. A.; Pripadchev, D.; Sagyan, A.
S.; Beck, A. K.; Seebach, D. ARKIVOC 2004, 132−150.
(33) Pandiaraju, S.; Chen, G.; Lough, A.; Yudin, A. K. J. Am. Chem.
Soc. 2001, 123, 3850−3851.
(34) Birchall, J. M.; Haszeldine, R. N.; Parkinson, A. R. J. Chem. Soc.
1961, 2204−2206.
(35) Haynes, W. M., Ed. Dissociation Constants of Organic Acids
and Bases. In CRC Handbook of Chemistry and Physics, 94th ed.; CRC
Press: Boca Raton, FL, 2013.
(36) Uyeda, C.; Jacobsen, E. J. Am. Chem. Soc. 2008, 130, 9228−
9229.
(37) Koppel, I.; Koppel, J.; Leito, I. J. Phys. Org. Chem. 1996, 9, 265−
268.
(38) (a) Jensen, K. H.; Sigman, M. S. J. Org. Chem. 2010, 75, 7194−
7201. (b) Jensen, K. H.; Sigman, M. S. Angew. Chem., Int. Ed. 2007, 46,
4748−4750. (c) Nickerson, D. M.; Angeles, V. V.; Auvil, T. J.; So, S.
S.; Mattson, A. E. Chem. Commun. 2013, 49, 4289−4291.
(39) Li, X.; Deng, H.; Zhang, B.; Li, J.; Zhang, L.; Luo, S.; Cheng, J.-
P. Chem.Eur. J. 2010, 16, 450−455.
(40) (a) Hine, J.; Linden, S.-M.; Kanagasabapathy, V. M. J. Am.
Chem. Soc. 1985, 107, 1082−1083. (b) Hine, J.; Linden, S.-M.;
Kanagasabapathy, V. M. J. Org. Chem. 1985, 50, 5096−5097.
(41) Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K. M.; Schreiner, P.
R. Org. Lett. 2012, 14, 1724−1727.
(21) (a) So, S. S.; Burkett, J. A.; Mattson, A. E. Org. Lett. 2011, 13,
716−719. (b) So, S. S.; Mattson, A. E. J. Am. Chem. Soc. 2012, 134,
8798−8801. (c) So, S. S.; Auvil, T. J.; Garza, V. J.; Mattson, A. E. Org.
Lett. 2012, 14, 444−447. (d) Auvil, T. J.; So, S. S.; Mattson, A. E.
Angew. Chem., Int. Ed. 2013, 52, 11317−11320. (e) Hardman, A. M.;
So, S. S.; Mattson, A. E. Org. Biomol. Chem. 2013, 11, 5793−5797.
(f) So, S. S.; Oottikkal, S.; Badjic, J. D.; Hadad, C. M.; Mattson, A. E. J.
Org. Chem. 2014, 79, 4832−4842.
(42) Ni, X.; Li, X.; Wang, Z.; Cheng, J.-P. Org. Lett. 2014, 16, 1786−
1789. (b) Kaupmees, K.; Tolstoluzhsky, N.; Raja, S.; Rueping, M.;
Leito, I. Angew. Chem., Int. Ed. 2013, 52, 11569−11572.
(43) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Part A:
Structure and Mechanisms, 5th ed.; Springer: New York, 2007; pp 348−
354.
(22) Takenaka, N.; Sarangthem, R. S.; Seerla, S. K. Org. Lett. 2007, 9,
2819−2822.
J
dx.doi.org/10.1021/ja5086244 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(44) Values of ln(krel) are plotted for continuity in Figures 11 and 12.
Numerical α value listed in the text were obtained from plots of
log(krel) in accord with eq 4.
(45) Harper, K. C.; Sigman, M. S. J. Org. Chem. 2013, 78, 2813−
2818.
K
dx.doi.org/10.1021/ja5086244 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX