ARTICLES

PUBLISHED ONLINE: 18 MARCH 2012 | DOI: 10.1038/NCHEM.1297

Multidimensional steric parameters in the analysis

of asymmetric catalytic reactions
Kaid C. Harper, Elizabeth N. Bess and Matthew S. Sigman*

Although asymmetric catalysis is universally dependent on spatial interactions to impart specific chirality on a given
substrate, examination of steric effects in these catalytic systems remains empirical. Previous efforts by our group and
others have seen correlation between steric parameters developed by Charton and simple substituents in both substrate
and ligand; however, more complex substituents were not found to be correlative. Here, we review and compare the steric
parameters common in quantitative structure activity relationships (QSAR), a common method for pharmaceutical function
optimization, and how they might be applied in asymmetric catalysis, as the two fields are undeniably similar. We
re-evaluate steric/enantioselection relationships, which we previously analysed with Charton steric parameters, using the
more sophisticated Sterimol parameters developed by Verloop and co-workers in a QSAR context. Use of these Sterimol
parameters led to strong correlations in numerous processes where Charton parameters had previously failed. Sterimol
parameterization also allows for greater mechanistic insight into the key elements of asymmetric induction within
these systems.

but it has been applied to asymmetric catalysis only recently23,26–28.

T
he challenges of asymmetric catalyst development were aptly
articulated by Nobel laureate William Knowles when he
wrote, ‘Since achieving 95% [enantiomeric excess] only
involves energy differences of about 2 kcal [per mol], which is no
more than the barrier encountered in a simple rotation of ethane,
it is unlikely that before the fact one can predict what kind of
ligand structures will be effective’1. True to this statement, asym-
metric catalyst design and optimization has been dominated by
empirical observations, and predicting enantioselective outcomes
remains a primary goal for those designing and studying asymmetric
catalytic systems. To generate predictive power, the small energetic
differences in diastereomeric transition states (to which Knowles
made reference) must be systematically scrutinized. Probing these
transition states using physical organic and computational tech-
niques has shed substantial light on the mechanisms of asymmetric
induction, providing motivation for predictive catalyst design2–15.
Specifically, recent reports using computational techniques for
determining and defining non-covalent, attractive interactions in
organocatalysis have provided insight for elucidating the key roles
of these interactions in determining reactivity and enantioselectiv-
ity4,16–19. Similarly, X-ray crystallography mapping of chiral infor-
mation remains a useful tool for deducing enantioselectivity in
systems that can be studied with this method (that is, asymmetric cat-
alytic reactions with reasonably well-understood catalyst struc-
tures)20,21. Complementary to these computational techniques, we
have pursued an alternative approach for investigating asymmetric
catalytic mechanisms using classic physical organic chemistry prin-
ciples in tandem with systematically manipulated catalysts.
Steric effects are widely implicated in asymmetric induction3,22, so
we began to examine methods by which steric effects in enantioselec-
tive reactions could be quantitatively defined23. Requisite to develop-
ing steric effect-based linear free energy relationships (LFERs) was
the consideration of two key challenges: (i) developing modular
ligand scaffolds with which meaningful systematic perturbations
could be executed24,25 and (ii) numerically quantifying steric effects
for the synthetically accessible substituents. Steric parameterization
based on experimental results has been studied for over 60 years,
However, the related discipline of quantitative structure–activity
relationships (QSAR) is particularly adept in the application, refine-
ment and development of steric parameters so as to fundamentally
understand the spatial interactions of small molecules in biological
systems29. The principles and parameters developed in these QSAR
studies hold considerable potential for application in asymmetric cat-
alysis, as the two fields are undeniably similar5,6. Although substitu-
ent effects can be multifaceted, in contrast to QSAR studies we have
focused on the repulsive steric effects that prevail in small-molecule
catalyst–substrate complexes. Our aim has therefore been to apply
selected QSAR principles and steric parameters to asymmetric cata-
lysis to expose the key elements responsible for asymmetric induc-
tion, which will ultimately provide a platform for de novo catalyst
design. We also describe the application and evaluation of sophisti-
cated steric parameters originally reported by Verloop30 to correlate
ligand and substrate steric effects to enantioselective reaction
outcome(s). Using Verloop’s parameters has enhanced our ability
to draw correlations between steric effects and enantioselection
(previously untenable using Charton/Taft steric parameters) and
has provided insight into the origin of these effects.
Classical steric parameters
The quantification of steric effects has been a source of some con-
troversy. Several different parameter sets have been developed,
both experimentally and computationally, and applied with
varying degrees of success in biological and chemical settings.
Assessing the origin and derivation of some of the most widely
known parameters yields insight into how and when they may
appropriately be used. The revered Winstein–Holness values
(A-values, Fig. 1a)31, the most widely recognized set of steric para-
meters, arise from the conformational study of mono-substituted
cyclohexane rings. A-values are based on the observed equilibrium
of conformers in mono-substituted cyclohexane rings, where per-
turbation of this equilibrium is presumably due to 1,3-diaxial
steric repulsion. Interference values are another example of an
experimentally determined steric parameter and are based on the

Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, USA. * e-mail: sigman@chem.utah.edu

366 NATURE CHEMISTRY | VOL 4 | MAY 2012 | www.nature.com/naturechemistry

© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1297 ARTICLES
a
Winstein–Holness parameter (A-value) Tolman cone angles

R R
R R R

Interference values Taft steric effects

H H
O H3O O
Δ
CH3
CH CH R O R OH
CH3 3 CH3 3
R R H H
O O
CH3 Rate-determining step CH3
R O O
R
H OH2
b O
Sterimol parameters
CH3
R O
H
O
B5
H
L
1
B

c 2.5 d
Interference value Charton value
2.0 2 Sterimol value
A-value
Charton value
1.5
Molar refractivity
1.0 Tolman cone angle 1
z-score
z-score

0.5

0.0 0

–0.5

–1.0 –1

–1.5

–2.0 –2
H Me Et Ph i-Pr Cy t-Bu
Ph
Bn

Bu
e

H 2
r
y
Pr

)2

3
C Pr
Et

C 2t

Et
H

H d
i-P

E
t-B

Pr
M

A
2 i-

H
H

C
2 t-

(i-

Substituent
C
H
C

Substituent

Figure 1 | Visualization of the experimental basis of several steric parameters and comparison of their determined values. a, Experimental basis for
common parameters. The Winstein–Holness parameter (A-value) is derived from the equilibrium position of ring flipping in a monosubstituted cyclohexane.
Interference values are derived from the half-life of thermal racemization in a 2,2′ -substituted biphenyl system. Tolman cone angles may be limited to the
description of steric bulk in phosphine ligands. Taft steric effects are derived from the relative rates of hydrolysis in methyl esters. b, Unlike other steric
pararmeters, Sterimol parameters assign three values to steric bulk: B1 and B5 are the minimum and maximum widths of the group when viewed in profile
looking down the primary axis and L is the total length along the same axis (illustrated here for a 1,2-dimethylpropyl group). c, Normalized comparison of
these steric parameters. d, Comparison of normalized Charton values and Sterimol B1 values, showing significant divergence for bulky substituents.

heat-induced half-life of racemization in 2,2′ -substituted biphenyl
systems32,33. The steric interaction between the substituent R and
the opposing aryl ring is presumed to be the key factor responsible
for the different energies required for racemization of the atrop-
isomers. Molar refractivity, a steric parameter found in many
early QSAR studies29, is defined by the Lorentz–Lorenz equation
and has proven to be an adequate descriptor of total steric volume
but disregards molecular shape29. Another steric parameter that
has had a wide impact on the organometallic community is the
Tolman cone angle34,35. Tolman and others have measured the
projected cone angle of phosphinyl substituents from a hypothetical
metal centre36,37. However, the scope of this parameterization may
be limited to phosphine ligands.
A widely used steric parameter in QSAR studies and other
branches of chemistry is the Taft parameter38,39. Taft developed
these parameters in his efforts to delineate steric effects from
electronic effects in aliphatic ester hydrolysis, by means analogous
to those used to derive Hammett’s electronic parameters40. Taft
elegantly hypothesized that, under acid-catalysed conditions, the
preservation of charge through the rate-determining step would

NATURE CHEMISTRY | VOL 4 | MAY 2012 | www.nature.com/naturechemistry 367

© 2012 Macmillan Publishers Limited. All rights reserved.

ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.1297

diminish any inductive or resonance electronic contributions 10 mol% CrCl3•(THF)3

O 10 mol% 1 HO H(Me)
from the R substituent. Thus, any variation in the rate of hydro- + Br
lysis would be proportional to the steric repulsion of the approach- Ph H(Me) 20 mol% TEA, Ph
2 equiv. 2 equiv. TMSCl
ing nucleophile. Taft’s original experimental results have been 2 equiv. Mn(0),
manipulated and redefined in many studies, resulting in various THF, RT

sets of Taft-based steric parameters41–44. Most notably, Charton

O
found a correlation between Taft’s experimentally measured rates
and the calculated minimum van der Waals radii of each symmetri- O
N
H
cal substituent45–47. Charton corrected the experimental values of N N
O
the non-symmetrical substituents to agree with the calculated Bn 1
van der Waals radii, creating a set of computational, but experi- O
X
mentally rationalized, parameters. Hansch validated Charton’s
parameters by extrapolating Charton’s correlation to previously
unmeasured substituents, finding agreement between predicted Benzaldehyde t-Bu
and measured values48. 2.0 Acetophenone
1-Ad

Enantioselectivity ΔΔG‡ (kcal mol–1)

Comparison of classical steric parameters 1.5
The variety of methods by which these steric parameters have been CEt3
obtained can lead to uncertainty regarding how and when to apply 1.0 i-Pr
them in asymmetric catalysis (or other applications). Comparison of
the normalized (z-score) values derived from the five sets of para- CH(i-Pr)2
0.5 Et
meters reveals some innate similarities for the simplest substituents CH(Pr)2
(Fig. 1c). The congruency among Interference, A-, Tolman and
Me
Charton values, despite the various means used to define them, 0.0
suggests these parameters are measuring the same general steric
factor. Molar refractivity values do not agree with the other three –0.5
parameters as closely, but the same general trends are observed.
The broad consistency observed in Fig. 1c also advocates that
–1.0
selection of the parameter set should be of minimal consequence 0.3 0.6 0.9 1.2 1.5 1.8 2.1 2.4
when examining simple steric effects. The inherent similarity in Charton value, ν
the parameters suggests that all would be equally robust steric
descriptors. Therefore, when selecting a parameter set for describing Figure 2 | NHK allylations of benzaldehyde and acetophenone using
steric bulk, the primary consideration would be for which set have standard conditions. The steric-based free energy relationship derived using
the substituents under evaluation been parameterized, not necess- Charton steric parameters, showing breaks in linearity for substituents
arily how the parameters were determined. This consideration is with large Charton values. Me ¼ CH3 , Et ¼ CH2CH3 , Pr ¼ CH2CH2CH3 ,
apparent in the QSAR literature—Taft-based steric parameters are i-Pr ¼ CH(CH3)2 , t-Bu ¼ C(CH3)3 , 1-Ad ¼ 1-adamantyl. TEA, triethylamine;
most prevalent, coincident with their extensive parameter library. THF, tetrahydrofuran; RT, room temperature.

Sterimol parameters An additional attractive feature of Sterimol parameters is

In the 1970s, Verloop and co-workers viewed the similarities
between the parameters described above as a fundamental
deficiency30. Moreover, application of these simple parameters can
fail (vide infra) to provide meaningful steric-based LFERs, most
probably due to the multifaceted nature of the steric effects.
Accordingly, Verloop developed the Sterimol program30,49–51,
which calculates several dimensional properties for a single substitu-
ent, based on Corey–Pauling–Koltun atomic models52,53. Rather
than group all of the spatial information into a single cumulative
value, Verloop created subparameters, each of which describes a
different dimensional property of interest (Fig. 1b). Verloop para-
meters contain three subparameters: two width parameters (B1
and B5) and a length parameter (L). The different width subpara-
meters were calculated according to the profile of the substituent
when viewed down the axis of the primary bond (Fig. 1b). The B1
parameter describes the minimum profile width of the substituent
from the primary bond axis, and the B5 parameter describes
the maximum width from the same axis. With B1 defined as the
minimum width perpendicular to the primary bond axis, its value
can generally be considered a function of branching at the first
carbon centre. That is, methyl has a smaller B1 value than singularly
substituted carbons (for example, ethyl, propyl), and B1 values get
larger with increasing substitution, that is, from di-substituted (for
example, isopropyl) and then to quaternary carbons. The length
parameter is the total length of the substituent along the primary
bond axis. Verloop has seen widespread success in applying these
parameters in QSAR studies49–51.
that they are reported in dimensional units (Å), which provides
more detailed information about the nature of a steric effect.
More specifically, identifying the relationship between enantioselec-
tivity and Sterimol values results in slope coefficients with units of
kcal mol21 Å21. The energy/distance ratio implicates a repulsive
steric interaction, which is widely invoked within asymmetric cata-
lysis as a rationale for chirality transfer, supporting the potential
application of these parameters54–56.
Comparison of Sterimol and Charton parameters
The manner in which the B1 parameter of the minimum width of a
substituent differs from the minimal van der Waals radius allows for
some unique inferences. In determination of the minimum van der
Waals radius, rotation about the primary bond of the substituent is
considered, and the minimum radius is essentially the effective
width of the substituent through this rotation. The result of this
treatment is that substituents are generalized as spherical.
Therefore, Charton’s correlation of minimum van der Waals radii
to the relative rate of ester hydrolysis strongly suggests that this
bond rotation is kinetically faster than the rate of nucleophilic
attack in the hydrolysis reaction. Sterimol parameters do not rely
on this correlation. Hence, application of the Sterimol parameters
to asymmetric catalytic systems could take advantage of the added
information contained in the Sterimol parameters to evaluate tran-
sition state structure(s) and other key structural features affecting
asymmetric induction. To explore the potential of Sterimol par-
ameters in asymmetric catalysis, in the following, we report a

368 NATURE CHEMISTRY | VOL 4 | MAY 2012 | www.nature.com/naturechemistry

© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1297 ARTICLES
re-evaluation of several of the systems that we studied previously Rotational effects on Charton parameters
and compare the results. H
O OH
OMe
Limitations of Charton parameters R1 knu R1
OMe OH2
Initially, we became interested in using steric parameters to quantify R2 R2
R3 R3
empirical trends observed while exploring a modular ligand scaffold
(1) for the asymmetric catalytic Nozaki–Hiyama–Kishi (NHK) ally-
lation of carbonyls (Fig. 2)23,24. Systematic optimization of the ligand
scaffold revealed a pronounced effect of different carbamoyl moie-
ties on the enantioselectivity of the reaction. Using Charton H OH
O OMe
parameters, we were able to construct several different LFERs that
R3 knu R3
relate enantioselectivity to the steric influence of carbamoyl substi- OMe OH2
R1
tuents (Fig. 2). Extrapolation of the initial linear regressions predicts R1 R2
R2
that incorporating a large carbamoyl substituent would generate
increasing levels of enantioselectivity. This hypothesis led us to syn-
thesize large carbamoyl moieties and evaluate them in the allylation krot
of benzaldehyde and acetophenone. Unfortunately, these ligands
delivered poorer enantioselectivities, in discord with extrapolative H OH
O OMe
expectations (Fig. 2). knu R2
R2
Breaks in linearity observed in LFERs using the Hammett OMe OH2
R3
electronic parameters are often simply interpreted as a change in R3 R1
R1
the overall reaction mechanism or rate-limiting step57,58. An alternative
interpretation of a perceived break in linearity is that the parameter Inherent assumption
used does not adequately describe the origin of the effect under evalu- H H
ation, as a single value describes resonance, field and inductive O O
effects59. For example, Hammett s values can fail for a system in R1 R1 ≠ R2 ≠ R3
which only inductive effects are applicable60,61. A more refined R2
OMe
krot >> knu R OMe
approach has been taken in cases where s values fail to produce ade- R3
quate correlations; electronic subparameterizations have been reported
by Swain–Lupton and Taft–Topsom, where resonance effects are Scaled sphere approximations
differentiated from field effects in multiparameter systems29,62–64.
In our study of steric effects using Charton values, we initially
interpreted the breaks in linearity shown in Fig. 2 as a change in Me Et i-Pr t-Bu CH(Pr)2
the mechanism of asymmetric induction, either by global confor-
mational shift of the ligand/catalyst structure or congestion of the
catalyst active site, leading to reaction at a different coordination
Figure 3 | The Charton steric parameter is experimentally based and has
site65. However, we also considered that this observed break in lin-
inherent limitations. The nature of the Charton parameter implies that krot
earity was potentially due to an imperfect application of the
must be much greater than knu to approximate substituents as spheres
Charton parameters.
(shown in relative scale).
Such a possibility demands a more detailed discussion of the
Charton parameter. The correlation of van der Waals radii to
Taft’s parameters provides compelling evidence for free rotation is that a single (rotational) conformation provides the lowest
about the primary bond in acid-catalysed ester hydrolysis (Fig. 3). energy pathway for non-symmetrical substituents, and this confor-
In cases where R1 = R2 = R3 , and krot is much greater than knu mation is not likely to be approximated as a sphere (that is, krot ≪
(Fig. 3), then rotation about this bond allows substituents to be knu). In all, Charton’s spherical assumption is a limiting premise
described as spheres; in other words, this parameterization when the substituent is not symmetrical about the primary bond
implies that the specific bond rotation is significantly faster than (R1 = R2 = R3). For groups with symmetry about the primary
the rate-determining step of hydrolysis. bond (R1 ¼ R2 ¼ R3), a spherical model based on minimum van
In an enantioselective reaction under kinetic control, consider- der Waals radii more reasonably describes their steric influence in
ation of the Curtin–Hammett principle is critical in that all a transition state. However, in our initial studies involving
catalyst–substrate conformers in pre-equilibrium, even rotational Charton parameters, a linear correlation for non-symmetrical
conformers, do not affect enantioselectivity. Only the differential groups smaller than 1-adamantyl is observed. Why do Charton’s
energy associated with the diastereomeric transition states is parameters seem to fit when smaller substituents are used? A poss-
responsible for enantiomeric excess. The energy difference is, as ible explanation could be that the Charton parameters for ethyl and
Knowles articulated, the principle challenge of designing asym- isopropyl are close approximations to the conformationally
metric catalysts. Invoking steric effects generally implies that restricted size, but for larger groups, the disparity between
many possible diastereomeric transition states are destabilized by Charton’s approximation of the substituent size and the confor-
repulsive interactions, creating the energy difference resulting in mationally restricted steric effect is exacerbated (support for this
an enantiomeric excess. The steric destabilization of diastereomeric statement can be found in Supplementary Table S11).
transition states is related to the operating catalyst–substrate Sterimol parameters, in contrast, are not based on a mechanisti-
conformations approaching the transition state, which is generally cally discrete reaction. The minimum width, as described by the
simplified to a single low-energy conformer. Sterimol parameter B1 , approximates the repulsive effect of a
Juxtaposed to the Curtin–Hammett principle, application of the lowest energy conformer where steric repulsion might occur
Charton parameter assumes a net conformer for the specific tran- between a substituent and a substrate. The dependence of enantios-
sition state, although the difference in energy of these rotational electivity on both minimum and maximum width parameters (B1
conformers is potentially high. A more probable general scenario and B5) could approximate a less-defined transition state and/or

NATURE CHEMISTRY | VOL 4 | MAY 2012 | www.nature.com/naturechemistry 369

© 2012 Macmillan Publishers Limited. All rights reserved.

ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.1297

Table 1 | Arranging the common carbon substituents functionality is crucial for achieving highly enantioselective NHK
according to Charton value (y ) and Sterimol B1 value reactions using this ligand scaffold. This sensitivity towards proxi-
demonstrates their divergence with larger substituents. mal bulk, taken with the suggested static nature of the catalyst,
suggests that the carbamoyl group is closely associated with the cat-
Charton parameters B 1 Sterimol parameters alyst coordination site where facial selection is occurring—possibly
Group Value Group Value through electrostatic attraction. The model also indicates that a
H 0 H 1 group with large proximal steric bulk should generate high enantio-
Me 0.52 Me 1.52 selectivity, whereas distal steric bulk (associated with the statistically
Et 0.56 Et 1.52 insignificant B5 term) would have little effect on the reaction
Ph 0.57 Bn 1.52 outcome. Accordingly, the NHK reaction employing the 1-adamantyl
Bn 0.7 CH2i-Pr 1.52 ligand, which has a large calculated B1 value, gave the highest
i-Pr 0.76 CH2t-Bu 1.52
observed enantioselectivity.
Cy 0.87 Ph 1.71
CH2i-Pr 0.98 i-Pr 1.9
Re-evaluation of the NHK allylation of acetophenone, using Sterimol
t-Bu 1.24 CHPr2 1.9 parameters in the multivariate regression, yielded equation (2),
Ad 1.33 Cy 1.91
CH2t-Bu 1.34 CH(i-Pr)2 2.08 DDG‡ = −1.67 + 0.73B1 (2)
CHEt2 1.51 CHEt2 2.13
CHPr2 1.54 t-Bu 2.6 Figure 4b depicts how using the Sterimol parameters again provides
CH(i-Pr)2 1.7 CEt3 2.94 a linear correlation, in contrast to that observed using Charton
CEt3 2.38 Ad 3.16 parameters (Fig. 2). The model with the highest degree of statistical
significance uses only the B1 parameter to correlate enantioselectivity,
indirect steric repulsion and its contribution towards conformation- again indicating close association of the carbamoyl group.
al rigidity. A comparison of the normalized values (z-score) of In NHK allylations of both benzaldehyde and acetophenone, the
Charton and B1 parameters highlights the difference between the Sterimol parameters provide models with greater correlative power
two sets of parameters, especially for groups larger than cyclohexyl than the Charton-based models. These results also indicate that
(Cy) (Fig. 1c and Table 1). As with our previous comparison of our previous conclusions based on the Charton analysis were erro-
steric values, the values of the simple, symmetric substituents do neous; a global catalyst change in conformation or activity is no
not differ significantly between the Charton and B1 parameters. longer consistent with the data. The limitations of the Charton
Examining the larger, non-symmetrical substituents, the incongru- parameters resulted in misrepresentation of the data.
ity between the two sets of parameters becomes more apparent, par-
ticularly when comparing the order of relative size. Sterimol analysis of substrate steric effects
Our laboratory was recently involved in a collaborative study with
Sterimol analysis of NHK reactions the Miller group at Yale, seeking to elucidate the role of substrate
It was our suspicion of the Charton parameters in the roles to which steric effects in the peptide-catalysed desymmetrization of bisphe-
we were applying them that prompted us to reassess our data using nols, as depicted in Fig. 5a67,68.
the Sterimol parameters. Examination of the data collected for the Previous analysis of the steric influence of the R group of the sub-
enantioselective NHK allylation reactions using the Sterimol par- strates showed a linear correlation with DDG ‡ values when modelled
ameters presented some new challenges in data analysis. Relating with A-, Charton and Interference values for simple, generally sym-
the three subparameters to their influence on the enantioselective metrical substituents (Fig. 5b, triangular data points, dashed line),
outcome relies on the analysis of a four-dimensional data set. To but this analysis was limited by a lack of available parameter
delineate this, mathematical models were developed by multivariate values. Synthesis of an extensive set of substrate analogues and sub-
linear least-squares regression and refined based on a P-test evalu- sequent evaluation with Charton parameters showed little or no cor-
ation of each parameter and its coefficient66. Parameter coefficients relation to enantioselectivity (Fig. 5b, all data points). This unique
failing the P-test of statistical significance were eliminated from the example of a steric effect so remote from the site of reaction is
model until the maximum statistical significance was evolved, as well suited to Sterimol analysis, which can attempt to define what
determined primarily by F-test statistics as well as cumulative key interactions contribute to the observed enantioselectivity.
P-values (a full explanation of the methods used to derive this Re-evaluating the data using the Sterimol parameters furnished
model and all subsequent models and cross-validation can be the following model (equation (3)):
found in the Supplementary Information).
Re-evaluation of the benzaldehyde NHK allylation data set using DDG‡ = −0.418 + 0.929B1 − 0.109L (3)
Sterimol parameters produced equation (1),
For this reaction, the model dictates the B5 term as statistically
DDG‡ = −1.068 + 0.938B1 (1) insignificant, and inclusion of B1 and L terms results in a planar
surface relating the minimum width and length of a substituent to
which includes only two statistically significant terms—the enantioselectivity and dictates that the optimal substrate would
minimum width parameter (B1) and the offset ( y-intercept)—and have an R group with a large minimum width and a short length.
is plotted in Fig. 4a. Use of only the B1 subparameter models the The use of Sterimol parameters creates a strong correlative model
data without a break in linearity for larger substituents, unlike the (Fig. 5c), further demonstrating the robustness of Sterimol-based
model generated using Charton parameters (Fig. 2). The robustness models in asymmetric catalytic applications. The model has a
of the Sterimol parameters in contrast to the failure of the Charton high degree of dependence on the B1 parameter, demonstrating
parameters is insightful for this system. This comparison indicates the need for proximal steric bulk. A small but significant negative
that the carbamoyl group is better modelled as static, rather than effect on enantioselectivity is incurred for substituents with larger
conformationally dynamic, in its influence on enantioselectivity. length parameters. Of the possible mechanisms through which
Given that, for the substituents evaluated, B1 is a measure of this asymmetric induction may occur, these results seem to impli-
proximal steric bulk, interpretation of the dependence of the cate the previously hypothesized propeller-like twist of the aryl
model on B1 suggests that steric bulk proximal to the carbamate rings by interaction with a proximally large substituent.

370 NATURE CHEMISTRY | VOL 4 | MAY 2012 | www.nature.com/naturechemistry

© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1297 ARTICLES
a 2.5 a R 2.5 mol% 2 R
ΔΔG‡ = 0.938B1 – 1.068 2 equiv. Ac2O

CHCl3. –35 º C, 20 h
Enantioselectivity ΔΔG‡ (kcal mol–1)

R2 = 0.86
2.0 t-Bu 1-Ad HO OH HO OAc

CH3
1.5 N
N
CEt3 O O Ph
H H
N N Ph
1.0 i-Pr BocHN N N
H H
Isopropyl-like O O O NHTs
CH(i-Pr)2 Ot-Bu
substituents
TrtHN 2
0.5 Et CH(Pr)2

b 2.0
Me
ΔΔG‡ = 1.36ν – 0.10 1-Ad
0.0 1.8

Enantioselectivity ΔΔG‡ (kcal mol–1)

1.6 2.0 2.4 2.8 3.2 R2 = 0.96
Sterimol minimum width, B1 1.6

b 0.75 1.4
ΔΔG‡ = 0.73B1 – 1.67 t -Bu

R2 = 0.88 1.2
Enantioselectivity ΔΔG‡ (kcal mol–1)

0.50 CHEt2
t-Bu 1-Ad
1.0
i-Pr
0.25 0.8 CHPh2
CEt3
Cyclohexyl
CH(i-Pr)2 0.6 Ph CH2t-Bu
0.00
Isopropyl-like 0.4 Et
Me
CH2Ph CH2i-Pr
substituents
–0.25 i-Pr 0.2
CH(Pr)2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
Charton value, ν
–0.50 c 2.0
Me y = 0.951x + 0.041
Et R2 = 0.95
–0.75
1.0 1.5 2.0 2.5 3.0 3.5
Predicted ΔΔG‡ (kcal mol–1)

Sterimol minimum width, B1 1.5

Figure 4 | Reanalysis of the data shown in Fig. 2 using Sterimol parameters.

a, Allylation of benzaldehyde data reassessed by regression with Sterimol
parameters, revealing the linear relationship between B1 and enantioselectivity. 1.0
b, Similar analysis using the allylation of acetophenone data. Propeller-like strain
R
Similarly, the strength of the Sterimol parameters in correlating
variation in the data suggests that there exists a preferred conformer
0.5
of the R group in relation to the chiral catalyst (that is, it cannot be
OH
treated as dynamic). However, the small negative dependence of the HO
enantioselectivity on substituent length also indicates that longer R 0.3 0.6 0.9 1.2 1.5 1.8
groups will weaken the substrate–catalyst interaction, leading to Measured ΔΔG‡ (kcal mol–1)
decreased levels of enantioselectivity. This suggests that the substrate
is bound such that the R group is arranged towards the catalyst and Figure 5 | Examination of substrate effects in the desymmetrization of
not away from it. This considerable simplification of the number of bisphenols. a, Desymmetrization of bishphenols with varied R groups under
possible transition states is not necessarily implied solely from the standard conditions. b, Using simple R groups, a linear correlation (dashed
suggested propeller mechanism. The relatively small value of the coef- line) is observed between Charton parameters and enantioselectivity;
ficient for the L parameter advocates that either the R group is some however, more rigorous examination of the R group revealed no correlation
distance away from the catalyst (incurring large repulsive penalties between Charton parameters and enantioselectivity. c, Re-analysis of the
only with extended substituents) or the R group is not oriented directly data used in b using Sterimol parameters leads to equation (3), which
into the catalyst but angled such that the steric effect is ancillary. demonstrates high correlation. The high correlation observed is suggestive of
Unlike other steric parameters, Sterimol parameter values are not the previously hypothesized propeller-strain mechanism for
based on relative rates but, instead, are distance calculations with asymmetric induction.
associated units (Å) potentially allowing for a more detailed under-
standing of the steric effect on enantioselectivity. Although the fol- Based on the above sentiment, a potentially useful and interest-
lowing interpretations rely on extrapolation of the model, a ing tool for delineating catalyst and substrate effects on enantio-
procedure that can only yield unsubstantiated conclusions, we selectivity is the substituent equivalence point (SEP): the
present these analyses as illustrations of the structural and/or enantioselectivity indicated by the model when competing substitu-
mechanistic clues that such analyses may provide. Additionally, ents are equivalent, reflecting the fundamental stereoselective bias
the correlation strength between measured and predicted DDG ‡ enacted on the substrate by the catalyst. For the desymmetrization
values (R 2 ¼ 0.95) decreases the danger of extrapolation, particu- of bisphenol, the competing substituents are the benzylic geminal
larly to data points near the source data. R and H. At the SEP, R ¼ H. Inserting the Sterimol values for a

NATURE CHEMISTRY | VOL 4 | MAY 2012 | www.nature.com/naturechemistry 371

© 2012 Macmillan Publishers Limited. All rights reserved.

ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.1297

hydrogen atom into equation (3) (B1 ¼ 1, L ¼ 2.06) leads to a differ- a 10 mol% CrCl3•(THF)3
ence in the Gibbs free energy of 0.29 kcal mol21. At first glance, this O Br 11 mol% 4 HO Me
evaluation appears to reflect model inaccuracy, as the product of Ph 2 equiv. 20 mol% TEA, Ph
4 equiv. TMSCl
such a reaction would be achiral. However, the true measured 2 equiv. Mn(0),
quantity in these analyses is the differential energy between the THF, RT, 24 h
diastereomeric transition states leading to an observed enantioselec-
Quinoline-proline ligand library
tivity. Thus, in the transition state for the substrate R ¼ H, the chiral O
catalyst–substrate interaction would render the methylene hydro- E E S
gens diastereotopic, so SEP analysis may reflect the energetic differ- N
H OMe Me
ences between these hydrogens as they interact with the catalyst. The N
O
N H t-Bu
calculated energy difference could reflect a stereoselective bias CF3 CEt3
O
inherent to the catalyst, which is subsequently imparted on the sub- 4 S
strate and amplified through greater substrate–catalyst repulsion
b 1.5
when R represents larger substituents. y = 0.973x + 0.050
SEP analysis is useful when applied to substrate–catalyst inter- R2 = 0.97
actions, as in the above example, but its extension to the previously
described NHK allylation systems becomes complicated by several

Predicted ΔΔG‡ (kcal mol–1)

factors, particularly the fact that the catalysts have several stereocen-
tres69. At this stage, it is suggested that SEP analysis is best-suited to
substrate effects on enantioselectivity.
More evidence for the proposed propeller-strain mechanism can
be found in extrapolation of the model to the y-intercept. The key
element of the propeller-strain mechanism is the difference in
steric bulk between the R group and its benzylic geminal hydrogen
atom. Extrapolating equation (3) to examine a purely hypothetical
situation in which the R group is much smaller than a hydrogen
atom, one would expect that the hydrogen atom would become
the dominant steric factor in the propeller mechanism. The shift
of dominant groups would be reflected by a change in sign of
the absolute configuration. Equation (3) reflects this change with
extrapolation to the y-intercept where B1 ¼ 0 and L ¼ 0, and the
estimated difference in the Gibbs free energy approaches
20.42 kcal mol21, which reflects the expected change in the
absolute configuration of the resultant chiral centre. Although this
is a conjectural example, the behaviour of the model parallels
the results expected if the propeller-strain mechanism is,
indeed, operative.
NHK propargylation of acetophenone
In our most recent report using steric parameters, we probed a
steric–electronic correlation in the NHK propargylation of aceto-
phenone70. Unsatisfactory evaluation of oxazoline-proline-based
ligand libraries led to the development of the QuinPro ligand
library (Fig. 6a). This ligand library allowed systematic electronic
and steric perturbations to be simultaneously evaluated, and the
results revealed an apparent strong correlation between electronic
and steric effects in the transition state(s). A resulting free-energy
surface was calculated from the equation describing the mathemati-
cal relationship of the parameters, which allows for quantitative
identification of the optimal ligand structure. The resultant steric–
electronic cross-relationship terms gave unique insight into the
interplay of these two reaction elements, which are traditionally
thought of as ‘independent’.
Re-evaluation of the QuinPro ligand library was performed
using Sterimol parameters in place of the Charton parameters we
initially reported. The base model included all the Sterimol
parameters, Hammett values and cross-terms relating each
Sterimol subparameter to the Hammett parameter. A backward-
elimination stepwise regression was then performed on the system
to generate equation (4):
DDG‡ = −0.696 + 1.83B1 − 0.962B5 − 2.705EB1 + 1.736EB5
(4)
In Fig. 6b, a slope value approaching unity shows the strong
correlative power of the Sterimol-based model. Equation (4) lacks
1.0
0.5
0.0
0.0 0.5 1.0 1.5
Measured ΔΔG‡ (kcal mol–1)
Figure 6 | Propargylation of acetophenone re-analysed using Sterimol
parameters in place of Charton parameters. a, Standard conditions for the
propargylation of acetophenone using the quinoline–proline ligand library.
b, Plot showing strong correlation between equation (4) derived from
Sterimol values and the observed enantioselectivity. TEA, triethylamine;
THF, tetrahydrofuran; RT, room temperature.
a solely electronic term and only gives significance to the electronic
parameter when paired with a steric component; the electronic
contribution to enantioselectivity is only effectual in tandem with
the steric effect of the carbamate. This observation can be rational-
ized by the fact that the electronic component alone does not
contain any chiral elements and cannot affect enantioselectivity
by itself; only in tandem with the steric effect is enantioselectivity
achieved. A possible explanation of this relationship as defined by
the Sterimol parameters is that decreasing the Lewis acidity of the
chromium centre is instrumental in decreasing the bonding distance
of the carbonyl to the chromium centre, thereby amplifying the
steric influence of the S group. The model shows a severe penalty
for combining substituents with large B5 values with electron-donat-
ing groups. This relationship suggests that larger substituents might
congest the reaction at the site responsible for high enantioselectiv-
ity, or extended steric repulsion might decrease the proximity of
chiral information to the site of enantioselection. In our previous
studies of this reaction, we concluded that the presence of the
cross-terms within the model gave evidence that steric and elec-
tronic effects were acting synergistically to affect enantioselectivity.
Use of the more refined Sterimol parameters gives more validity
to this relationship but also affirms that the steric effect is amplified
by the electronic effect and not vice versa.
To examine the predictive power of this model, a leave-one-out
(LOO) cross-validation was undertaken. LOO results for equation
(4) are given in Table 2, and regression of these predictions
results in q 2 ¼ 0.84.

372 NATURE CHEMISTRY | VOL 4 | MAY 2012 | www.nature.com/naturechemistry

© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1297 ARTICLES
Table 2 | LOO cross-validation data. information-rich models developed with Sterimol parameters for
NHK allylations also provide evidence for the specific steric
Ligand Averaged Experimental Predicted elements influencing enantioselectivity. Analysis of steric effects
observed DDG ‡ error DDG ‡ using Sterimol parameters in the desymmetrization of bisphenol
E ¼ CF3 S ¼ Me 20.10 0.04 20.23 sheds light on the mechanism of asymmetric induction and key sub-
S ¼ t-Bu 0.15 0.19 0.64 strate–catalyst interactions. Similarly, in the re-analysis of data gath-
S ¼ CEt3 0.26 0.03 0.58 ered in the propargylation of acetophenone, the Sterimol derived
E¼H S ¼ Me 0.09 0.03 0.15 model delineated which steric effect(s) were amplified and nullified
S ¼ t-Bu 1.12 0.03 0.97
through steric–electronic synergy. Outlined herein are several
S ¼ CEt3 0.73 0.06 0.65
E ¼ OMe S ¼ Me 0.24 0.003 0.31
examples where Sterimol models were found to be insightful and
S ¼ t-Bu 1.39 0.06 1.55 beneficial; however, in our studies, we identified limitations to
S ¼ CEt3 0.85 0.06 0.89 these parameters and their application, particularly in relation
to our previously published steric–steric three-dimensional relation-
ships (details of this analysis and some of the limitations of Sterimol
Deconstructing equation (4) into its individual elements, a parameters can be found in the Supplementary Information)69. Even
strong dependence on the B1 term is observed, as indicated by its so, Sterimol parameters, although imperfect, constitute a significant
large coefficient. The inclusion of a negative B5 term indicates that improvement in terms of overall utility and their ability to provide
substituents containing a large maximum radius would erode mechanistic insight into reactions. Information of this nature can be
enantioselectivity. The large negative coefficient relating B1 to E applied to developing and verifying stereochemical models, which is
suggests that the positive effects of proximal steric bulk on enantio- the crux of asymmetric catalyst development, and implementation
selectivity are amplified by electron-donating groups (negative of this information is our continuing goal.
Hammett values). The smaller but positive coefficient relating B5
and E indicates that the opposite effect is observed for large Received 18 November 2011; accepted 7 February 2012;
substituents. These two cross-terms suggest that the electronic published online 18 March 2012
nature of the catalyst influences the transition state, perhaps References
through a less Lewis acidic metal, allowing for a more product- 1. Knowles, W. S. Asymmetric hydrogenation. Acc. Chem. Res. 16,
like transition state, as alluded to in Jacobsen epoxidation catalysis 106–112 (1983).
and alkene difunctionalization reactions developed in our labo- 2. Cheong, P. H.-Y., Legault, C. Y., Um, J. M., Çelebi-Ölçüm, N. & Houk, K. N.
ratories71,72. This ultimately increases the proximal steric relevance Quantum mechanical investigations of organocatalysis: mechanisms,
reactivities, and selectivities. Chem. Rev. 111, 5042–5137 (2011).
of the S substituent. 3. Walsh, P. J. & Kozlowski, M. C. Fundamentals of Asymmetric Catalysis
Equation (4) was subjected to an optimizing algorithm to predict (University Science Books, 2009).
the key structural elements required for high enantioselectivity. The 4. Houk, K. N. & Cheong, P. H.-Y. Computational prediction of small-molecule
optimizing routine was bounded by the highest and lowest values catalysts. Nature 455, 309–313 (2008).
contained in the data set for the terms included in the model (B1 , 5. Denmark, S. E., Gould, N. D. & Wolf, L. M. A systematic investigation of
quaternary ammonium ions as asymmetric phase-transfer catalysts. Application
B5 and E). These bounds are necessitated by synthetic constraints, of quantitative structure activity/selectivity relationships. J. Org. Chem. 76,
as well as the inherent problems associated with multidimensional 4337–4357 (2011).
extrapolation. Applying this routine systematically across the 6. Denmark, S. E., Gould, N. D. & Wolf, L. M. A systematic investigation of
ligand space yielded identification of the same optimal ligand struc- quaternary ammonium ions as asymmetric phase-transfer catalysts. Synthesis
ture, indicating that the true global maximum was probably found. of catalyst libraries and evaluation of catalyst activity. J. Org. Chem. 76,
4260–4336 (2011).
The maximum indicated that the optimal ligand would contain the 7. Maldonado, A. G. & Rothenberg, G. Predictive modeling in homogeneous
largest possible B1 value (2.94), the smallest possible B5 value (2.04) catalysis: a tutorial. Chem. Soc. Rev. 39, 1891–1902 (2010).
and the most negative synthetically available Hammett value 8. Ianni, J. C., Annamalai, V., Phuan, P.-W., Panda, M. & Kozlowski, M. C. A priori
(20.27). The required Hammett value would be a strongly elec- theoretical prediction of selectivity in asymmetric catalysis: design of chiral
catalysts by using quantum molecular interaction fields. Angew. Chem. Int. Ed.
tron-donating group, which agrees with our previous results. The
45, 5502–5505 (2006).
optimized values for B1 and B5 are conflicting in terms of syntheti- 9. Kozlowski, M. C. & Panda, M. Computer-aided design of chiral ligands: Part I.
cally feasible substituents. However, the t-Bu group presents a Database search methods to identify chiral ligand types for asymmetric
reasonable tradeoff between a large B1 value and a small B5 value. reactions. J. Mol. Graphics Modell. 20, 399–409 (2002).
Not surprisingly, optimization of the Sterimol models yields 10. Kozlowski, M. C. & Panda, M. Computer-aided design of chiral ligands. Part 2.
Functionality mapping as a method to identify stereocontrol elements for
the same optimal ligand as the previous study, where E ¼ OMe asymmetric reactions. J. Org. Chem. 68, 2061–2076 (2003).
and S ¼ t-Bu. 11. Kozlowski, M. C., Waters, S. P., Skudlarek, J. W. & Evans, C. A. Computer-aided
design of chiral ligands. Part III. A novel ligand for asymmetric allylation
Conclusions designed using computational techniques. Org. Lett. 4, 4391–4393 (2002).
Sterimol parameters, as defined by Verloop, present a conceptually 12. Lipkowitz, K. B. & Kozlowski, M. C. Understanding stereoinduction in catalysis
via computer: new tools for asymmetric synthesis. Synlett. 2003, 1547–1565 (2003).
different approach to steric parameterization. A-, Interference and 13. Norrby, P.-O., Rasmussen, T., Haller, J., Strassner, T. & Houk, K. N.
Taft-based Charton values are experimentally verified parameteriza- Rationalizing the stereoselectivity of osmium tetroxide asymmetric
tions, but, as such, they are limited by the experimental conditions dihydroxylations with transition state modeling using quantum mechanics-
from which they were obtained. Verloop parameters are computa- guided molecular mechanics. J. Am. Chem. Soc. 121, 10186–10192 (1999).
tionally derived and may be a more suitable parameter for describ- 14. Oslob, J. D., Aakermark, B., Helquist, P. & Norrby, P.-O. Steric influences on
the selectivity in palladium-catalyzed allylation. Organometallics 16,
ing interactions in asymmetric catalysis due to their increased ability 3015–3021 (1997).
to describe non-symmetrical steric effects. Implementation of these 15. Brown, J. M. & Deeth, R. J. Is enantioselectivity predictable in asymmetric
parameters demonstrated general robustness in comparison to catalysis? Angew. Chem. Int. Ed. 48, 4476–4479 (2009).
Charton parameters. 16. Knowles, R. R. & Jacobsen, E. N. Attractive noncovalent interactions in
The comparison of models developed with Charton parameters asymmetric catalysis: links between enzymes and small molecule catalysts.
Proc. Natl Acad. Sci. USA 107, 20678–20685 (2010).
to those developed with Sterimol parameters demonstrates the 17. Uyeda, C. & Jacobsen, E. N. Transition-state charge stabilization through
strength of Sterimol parameters and highlights the detrimental multiple non-covalent interactions in the guanidinium-catalyzed enantioselective
assumptions applied in using Charton parameters. The Claisen rearrangement. J. Am. Chem. Soc. 133, 5062–5075 (2011).

NATURE CHEMISTRY | VOL 4 | MAY 2012 | www.nature.com/naturechemistry 373

© 2012 Macmillan Publishers Limited. All rights reserved.

ARTICLES
18. Zuend, S. J. & Jacobsen, E. N. Mechanism of amido-thiourea catalyzed
enantioselective imine hydrocyanation: transition state stabilization via multiple
non-covalent interactions. J. Am. Chem. Soc. 131, 15358–15374 (2009).
19. Jonsson, S., Odille, F. G. J., Norrby, P.-O. & Warnmark, K. Modulation of the
reactivity, stability and substrate- and enantioselectivity of an epoxidation
catalyst by noncovalent dynamic attachment of a receptor functionality—aspects
on the mechanism of the Jacobsen–Katsuki epoxidation applied to a
supramolecular system. Org. Biomol. Chem. 4, 1927–1948 (2006).
20. Lipkowitz, K. B., D’Hue, C. A., Sakamoto, T. & Stack, J. N. Stereocartography:
a computational mapping technique that can locate regions of maximum
stereoinduction around chiral catalysts. J. Am. Chem. Soc. 124,
14255–14267 (2002).
21. Lipkowitz, K. B., Sakamoto, T. & Stack, J. Using stereocartography for predicting
efficacy of stereoinduction by chiral catalysts. Chirality 15, 759–765 (2003).
22. Jacobsen, E. N., Pfaltz, A. & Yamamoto, H. Comprehensive Asymmetric Catalysis
I–III Vol. 1 (Springer, 1999).
23. Miller, J. J. & Sigman, M. S. Quantitatively correlating the effect of ligand–
substituent size in asymmetric catalysis using linear free energy relationships.
Angew. Chem. Int. Ed. 47, 771–774 (2008).
24. Miller, J. J. & Sigman, M. S. Design and synthesis of modular oxazoline ligands
for the enantioselective chromium-catalyzed addition of allyl bromide to
ketones. J. Am. Chem. Soc. 129, 2752–2753 (2007).
25. Miller, J. J., Rajaram, S., Pfaffenroth, C. & Sigman, M. S. Synthesis of amine
functionalized oxazolines with applications in asymmetric catalysis. Tetrahedron
65, 3110–3119 (2009).
26. Quintard, A. & Alexakis, A. 1,2-Sulfone rearrangement in organocatalytic
reactions. Org. Biomol. Chem. 9, 1407–1418 (2011).
27. Quintard, A., Alexakis, A. & Mazet, C. Access to high levels of molecular
complexity by one-pot iridium/enamine asymmetric catalysis. Angew. Chem.
Int. Ed. 50, 2354–2358 (2011).
28. Mantilli, L., Gérard, D., Torche, S., Besnard, C. & Mazet, C. Improved
catalysts for the iridium-catalyzed asymmetric isomerization of
primary allylic alcohols based on charton analysis. Chem. Eur. J. 16,
12736–12745 (2010).
29. Hansch, C. & Leo, A. Exploring QSAR: Fundamentals and Applications in
Chemistry and Biology (American Chemical Society, 1995).
30. Verloop, A. in Drug Design Vol. III (ed. Ariens, E. J.) 133 (Academic
Press, 1976).
31. Winstein, S. & Holness, N. J. Neighboring varbon and hydrogen. XIX.
t-Butylcyclohexyl derivatives. Quantitative conformational analysis. J. Am.
Chem. Soc. 77, 5562–5578 (1955).
32. Bott, G., Field, L. D. & Sternhell, S. Steric effects. A study of a rationally designed
system. J. Am. Chem. Soc. 102, 5618–5626 (1980).
33. Adams, R. & Yuan, H. C. The stereochemistry of diphenyls and analogous
compounds. Chem. Rev. 12, 261–338 (1933).
34. Niksch, T., Görls, H. & Weigand, W. The extension of the solid-angle concept to
bidentate ligands. Eur. J. Inorg. Chem. 95–105 (2010).
35. Tolman, C. A. Steric effects of phosphorus ligands in organometallic chemistry
and homogeneous catalysis. Chem. Rev. 77, 313–348 (1977).
36. Fey, N. et al. Computational descriptors for chelating P,P- and P,N-donor
ligands 1. Organometallics 27, 1372–1383 (2008).
37. Jover, J. S. et al. Expansion of the ligand knowledge base for monodentate
P-donor ligands (LKB-P)†. Organometallics 29, 6245–6258 (2010).
38. Taft, R. W. Jr. Polar and steric substituent constants for aliphatic and o-benzoate
groups from rates of esterification and hydrolysis of esters. J. Am. Chem. Soc. 74,
3120–3128 (1952).
39. Taft, R. W. Jr. Linear steric energy relationships. J. Am. Chem. Soc. 75,
4538–4539 (1953).
40. Hammett, L. P. Some relations between reaction rates and equilibrium constants.
Chem. Rev. 17, 125–136 (1935).
41. Fujita, T., Takayama, C. & Nakajima, M. Nature and composition of Taft–
Hancock steric constants. J. Org. Chem. 38, 1623–1630 (1973).
42. Hancock, C. K., Meyers, E. A. & Yager, B. J. Quantitative separation of
hyperconjugation effects from steric substituent constants. J. Am. Chem. Soc. 83,
4211–4213 (1961).
43. MacPhee, J. A., Panaye, A. & Dubois, J. E. Steric effects. 4. Multiparameter
correlation models. Geometrical and proximity site effects for carboxylic acid
esterification and related reactions. J. Org. Chem. 45, 1164–1166 (1980).
44. Sotomatsu, T. & Fujita, T. The steric effect of ortho substituents on the acidic
hydrolysis of benzamides. J. Org. Chem. 54, 4443–4448 (1989).
45. Charton, M. Steric effects. I. Esterification and acid-catalyzed hydrolysis of
esters. J. Am. Chem. Soc. 97, 1552–1556 (1975).
46. Charton, M. Steric effects. II. Base-catalyzed ester hydrolysis. J. Am. Chem. Soc.
97, 3691–3693 (1975).
374
© 2012 Macmillan Publishers Limited. All rights reserved.
NATURE CHEMISTRY DOI: 10.1038/NCHEM.1297
47. Charton, M. Steric effects. 7. Additional V constants. J. Org. Chem. 41,
2217–2220 (1976).
48. Kutter, E. & Hansch, C. Steric parameters in drug design. Monoamine oxidase
inhibitors and antihistamines. J. Med. Chem. 12, 647–652 (1969).
49. Verloop, A. & Tipker, J. in Biological Activity and Chemical Structure
(ed. Buisman, J. A.) 63 (Elsevier, 1977).
50. Verloop, A. & Tipker, J. in QSAR in Drug Dosing and Toxicology (ed. Hadzi. B. &
Jerman-Blazic, B.) 97 (Elsevier, 1987).
51. Verloop, A. in IUPAC Pesticide Chemistry Vol. 1 (ed. Miyamoto, J.) 339
(Pergamon, 1983).
52. Pauling, L. & Corey, R. B. Atomic coordinates and structure factors for two
helical configurations of polypeptide chains. Proc. Natl Acad. Sci. USA 37,
235–240 (1951).
53. Pauling, L. & Corey, R. B. Configurations of polypeptide chains with favored
orientations around single bonds. Proc. Natl Acad. Sci. USA 37, 729–740 (1951).
54. Jones, J. E. On the determination of molecular fields. I. From the variation of the
viscosity of a gas with temperature. Proc. R. Soc. A 106, 441–462 (1924).
55. Allinger, N. L., Yuh, Y. H. & Lii, J. H. Molecular mechanics. The MM3 force field
for hydrocarbons. 1. J. Am. Chem. Soc. 111, 8551–8566 (1989).
56. Lii, J. H. & Allinger, N. L. Molecular mechanics. The MM3 force field for
hydrocarbons. 3. The van der Waals’ potentials and crystal data for aliphatic and
aromatic hydrocarbons. J. Am. Chem. Soc. 111, 8576–8582 (1989).
57. Hammett, L. P. Physical Organic Chemistry (McGraw-Hill, 1940).
58. Anslyn, E. V. & Dougherty, D. A. Modern Physical Organic Chemistry
(University Science Books, 2006).
59. Jaffé, H. H. A reexamination of the Hammett equation. Chem. Rev. 53,
191–261 (1953).
60. Johnson, C. D. The Hammett Equation (University Press, 1973).
61. Exner, O. Advances in Linear Free-Energy Relationships (Plenum, 1972).
62. Swain, C. G. & Lupton, E. C. Field and resonance components of substituent
effects. J. Am. Chem. Soc. 90, 4328–4337 (1968).
63. Swain, C. G., Unger, S. H., Rosenquist, N. R. & Swain, M. S. Substituent effects
on chemical reactivity. Improved evaluation of field and resonance components.
J. Am. Chem. Soc. 105, 492–502 (1983).
64. Hansch, C., Leo, A. & Taft, R. W. A survey of Hammett substituent constants
and resonance and field parameters. Chem. Rev. 91, 165–195 (1991).
65. Sigman, M. S. & Miller, J. J. Examination of the role of Taft-type steric
parameters in asymmetric catalysis. J. Org. Chem. 74, 7633–7643 (2009).
66. Deming, S. N. & Morgan, S. L. Experimental Design: A Chemometric Approach,
2nd edn (Elsevier, 1993).
67. Gustafson, J. L., Sigman, M. S. & Miller, S. J. Linear free-energy relationship
analysis of a catalytic desymmetrization reaction of a diarylmethane-
bis(phenol). Org. Lett. 12, 2794–2797 (2010).
68. Lewis, C. A. et al. A case of remote asymmetric induction in the peptide-
catalyzed desymmetrization of a bis(phenol). J. Am. Chem. Soc. 130,
16358–16365 (2008).
69. Harper, K. C. & Sigman, M. S. Predicting and optimizing asymmetric catalyst
performance using the principles of experimental design and steric parameters.
Proc. Natl Acad. Sci. USA 108, 2179–2183 (2011).
70. Harper, K. C. & Sigman, M. S. Three-dimensional correlation of steric and
electronic free energy relationships guides asymmetric propargylation. Science
333, 1875–1878 (2011).
71. Palucki, M., Finney, N. S., Pospisil, P. J., Guler, M. L., Ishida, T. & Jacobsen, E. N.
The mechanistic basis for electronic effects on enantioselectivity in the
(salen)Mn(III)-catalyzed epoxidation reaction. J. Am. Chem. Soc. 120,
948–954 (1998).
72. Jensen, K. H., Webb, J. D. & Sigman, M. S. Advancing the mechanistic
understanding of an enantioselective palladium-catalyzed alkene
difunctionalization reaction. J. Am. Chem. Soc. 132, 17471–17482 (2010).
Acknowledgements
The authors thank Joel Harris for critical discussions on data analysis and Scott Miller
for access to data and insightful discussions regarding this work. Thanks also go to
Marisa Kozlowski for introducing us to Sterimol parameters. This work was supported
by the National Science Foundation (CHE-0749506 and CHE-1110599).
Author contributions
All authors discussed the results and commented on the manuscript.
Additional information
The authors declare no competing financial interests. Supplementary information
accompanies this paper at www.nature.com/naturechemistry. Reprints and permission
information is available online at http://www.nature.com/reprints. Correspondence and
requests for materials should be addressed to M.S.S.
NATURE CHEMISTRY | VOL 4 | MAY 2012 | www.nature.com/naturechemistry