Analyzing site selectivity in Rh2(esp)2-catalyzed intermolecular C-H amination reactions

Article abstract of DOI:10.1021/ja5015508

Predicting site selectivity in C-H bond oxidation reactions involving heteroatom transfer is challenged by the small energetic differences between disparate bond types and the subtle interplay of steric and electronic effects that influence reactivity. Herein, the factors governing selective Rh ₂(esp)₂-catalyzed C-H amination of isoamylbenzene derivatives are investigated, where modification to both the nitrogen source, a sulfamate ester, and substrate are shown to impact isomeric product ratios. Linear regression mathematical modeling is used to define a relationship that equates both IR stretching parameters and Hammett σ⁺ values to the differential free energy of benzylic versus tertiary C-H amination. This model has informed the development of a novel sulfamate ester, which affords the highest benzylic-to-tertiary site selectivity (9.5:1) observed for this system.

Full text of DOI:10.1021/ja5015508

Article
pubs.acs.org/JACS
Analyzing Site Selectivity in Rh2(esp)2‑Catalyzed Intermolecular C−H
Amination Reactions
Elizabeth N. Bess,†,∥ Ryan J. DeLuca,†,∥ Daniel J. Tindall,† Martins S. Oderinde,‡ Jennifer L. Roizen,‡,§
J. Du Bois,*,‡ and Matthew S. Sigman*,†
†Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
‡Department of Chemistry, Stanford University, 337 Campus Drive, Stanford, California 94305, United States
S
* Supporting Information
ABSTRACT: Predicting site selectivity in C−H bond
oxidation reactions involving heteroatom transfer is challenged
by the small energetic differences between disparate bond
types and the subtle interplay of steric and electronic effects
that influence reactivity. Herein, the factors governing selective
Rh2(esp)2-catalyzed C−H amination of isoamylbenzene
derivatives are investigated, where modification to both the
nitrogen source, a sulfamate ester, and substrate are shown to impact isomeric product ratios. Linear regression mathematical
modeling is used to define a relationship that equates both IR stretching parameters and Hammett σ+ values to the differential
free energy of benzylic versus tertiary C−H amination. This model has informed the development of a novel sulfamate ester,
which affords the highest benzylic-to-tertiary site selectivity (9.5:1) observed for this system.
substituent changes is linear free-energy relationship (LFER)
analysis.4 Pioneered by Hammett for electronic analysis of
meta- or para-substituted benzene rings5 and adopted by Taft6
and, later, Charton7 for steric effect analyses, these techniques
have been broadly applied to interrogate reaction outcomes.8
While these classic LFER parameters have been instrumental in
a variety of contexts, often illuminating mechanistic details by
relating log(K) to empirically derived electronic or steric
constants (where K may represent relative rate and equilibrium
constants, ratios of enantiomers and constitutional isomers,
etc.), LFERs also bear significant limitations;9 namely, there are
a modest number of reactions that can be successfully modeled
using Hammett or Taft/Charton parameters alone.9b,10
Over the last several years, the Sigman laboratory has inves-
tigated the use of discretely measured molecular parameters
(vide infra) as opposed to those derived from relative-rate ex-
periments (e.g., Hammett and Taft values) for nonclassic free-
energy relationship analysis, relating these parameters to ΔΔG‡
for differential transition state interrogation.9b,11 As the data
from the Rh-catalyzed C−H amination lacks obvious expla-
nation, commonly employed free-energy relationships are not
likely capable of delineating the entangled effects of the
sulfamate ester on site selectivity. Therefore, we have turned to
a recent discovery that specific infrared (IR) molecular vibra-
tions represent a broadly applicable, yet uniquely descriptive,
parameter set.10a IR vibrations can be computationally calcu-
lated for any molecule, the result of which is a tailored param-
eter set that is capable of describing the distinct nature of each
reactive species.
INTRODUCTION
■
Discriminate control over product selectivity in carbon−
hydrogen (C−H) bond functionalization reactions represents
one of the great challenges in modern synthetic chemistry.1
The high energy barriers to C−H bond cleavage (on the order
of 98 kcal mol−1) contrast the small energetic differences that
bias enantio- and chemoselective C−H bond functionalization
(ΔΔG‡ of ∼2 kcal mol−1 for >20:1 selectivity). Given the small
differences in transition state free energies that modulate
isomeric product ratios, it is often difficult to distinguish the
steric and electronic factors that influence reaction selectivity.
Identification of such factors, however, can prove invaluable for
tailoring catalyst and reagent structures to afford greater control
over reaction outcomes.
The Du Bois group recently reported an intermolecular Rh-
catalyzed C−H amination2 protocol and demonstrated that
oxidation of isoamylbenzene (a) results in benzylic-to-tertiary
(B:T) product ratios that are dependent upon the choice of
sulfamate ester b (Figure 1).3 The relationships between steric
and electronic factors that contribute to these disparate out-
comes are not obvious from the trends in selectivity. Spe-
cifically, sulfamate ester b1, R = CH2CCl3, yielded the highest
degree of B:T selectivity (8:1), while substitution to R = CH2t-
Bu (b2), a steric homologue, resulted in reduced benzylic
selectivity (4:1). An equally intriguing result was obtained from
the evaluation of sulfamate ester b3, R = CH(CF3)2, which
yields equimolar amounts of the two products. Similar losses
in selectivity were observed for both electron-poor (b4, R =
2,6-F2C6H3, 1.5:1) and electron-rich (b5, 4-t-BuC6H4, 1:1) aryl
sulfamate esters.
An archetypical physical organic technique for identifying
features that influence product selectivity as a function of
Received: February 13, 2014
Published: March 27, 2014
© 2014 American Chemical Society
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Figure 2. Twenty-membered sulfamate ester library used to probe the
reaction’s site-selection sensitivity. Ratios, determined by GC analysis,
are averaged over three experimental runs. Bolded and asterisked
sulfamate ester structures represent the DoE-defined subset of nitrene
sources.
interest, chlorine substitution (2e−2l) has a pronounced effect
on product selectivity with trichloromethyl sulfamate esters
(2k, 2l) yielding B:T ratios of ∼9:1, regardless of the proximity
of this group to the −SO2NH2 moiety. Relative to R = nBu
(2d), this same trend is maintained for di- and monochlor-
omethyl substrates, where B:T ratios average 5.3:1 (2i, 2j) and
4.5:1 (2e−2g), respectively.
Figure 1. (a) Rh2(esp)2-catalyzed C−H amination of isoamylbenzene,
demonstrating the sensitivity of site selection to the sulfamate ester
nitrene source. (b) Proposed mechanism for the amination reaction.
Herein, we exploit the intrinsic ability of IR vibrations to
describe the inherent molecular properties of sulfamate ester
nitrene precursors in selective Rh2(esp)2-catalyzed amination of
benzylic versus tertiary C−H bonds. Using IR-derived descrip-
tors to quantitate steric and electronic selectivity determinants,
we apply linear regression modeling to identify the sulfamate
ester features responsible for differential benzylic-to-tertiary
functionalization. Insights garnered from this free-energy model
have led us to design a new sulfamate ester, which yields the
highest selectivity ratio (9.5:1, B:T) reported, to date, for this
C−H amination process.
The insensitivity of B:T selectivity to chain length is a general
trend observed throughout the data set. The influence of steric
effects on selectivity becomes apparent when the sulfamate
ester bears a branched α-carbon (i.e., sulfamates prepared from
secondary alcohols). Specifically, selectivity for the benzylic
insertion product increases for iPrOSO2NH2 (2m, 7.0:1)
relative to EtOSO2NH2 (2b, 5.9:1). A marked change in the
product ratio is noted when halogen substituents are intro-
duced in these secondary alcohol-derived sulfamate esters (2h,
2n). For example, a reaction performed with (CF3)2CHOSO2-
NH2 yields nearly equal amounts of the benzylic and tertiary
products. However, replacing one CF3 group with H (2o,
7.4:1), to eliminate the branching pattern, rescues selectivity.
Parameter Selection. Collectively, the data portrayed in
Figure 2 reflect an ill-defined role for steric and electronic
modulation of the sulfamate ester on product selectivity. Steric
influences manifest principally in the narrow dimension of
branched versus nonbranched sulfamate groups. Additionally,
while inclusion of electronegative halogen atoms clearly alters
product selectivity, the effect cannot be ascribed entirely to
electronic differences in nitrenoid reactivity. These general fea-
tures of the amination reaction significantly complicate quan-
titative free-energy modeling of selectivity. Classic steric
parameters, such as Taft6 and Charton7 values and Winstein−
Holness (A) values12, derived from relative-rate and con-
formation equilibration experiments, respectively, treat sub-
stituent steric bulk as a spherical unit.9b Therefore, this
treatment has the disadvantage of averaging the nuances of
substituent asymmetry and width-to-length ratios into a single-
value representation of steric effects.
RESULTS AND DISCUSSION
■
Through the Du Bois group’s investigation of intermolecular
oxidation reactions (a proposed mechanism of which is
depicted in Figure 1b),2 an interesting relationship was noted
between the steric and electronic structure of the sulfamate
ester b and the B:T ratio in the oxidation of isoamylbenzene (a)
(Figure 1a).3 The results of these investigations were ascribed
principally to steric differences between sulfamate reagents, but
the influence of electronic substituent effects could not be dis-
counted. Accordingly, a sulfamate ester library was designed to
more thoroughly probe the interplay of steric and electronic
perturbations on the selectivity dependence of this system
(Figure 2). Library construction was based on two features
inspired by the original results: (1) the exploration of chain-
length and halogenation (2a−2l) and (2) the evaluation of
branching and steric bulk distal to the α-carbon of the sulfamate
(2m−2t).
Each of the sulfamate esters depicted in Figure 2 was evalu-
ated in the Rh2(esp)2-catalyzed amination of 1. Of particular
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In the development of free-energy relationships describing
selectivity, it is precisely these subtleties that are responsible
for the differential transition state energies leading to isomeric
product ratios, as predicated by the Curtin−Hammett prin-
ciple.13 Verloop innovatively approached this deficiency in
the description of steric effects through the development of
Sterimol parameters (Figure 3).14 This parameter set gives
Figure 4. Computationally derived IR spectrum for sulfamate ester 2a,
MeOSO2NH2. Vibrations used as modeling parameters are color-
coded, and graphical depictions approximating vibrational motions are
presented. Vibrational frequency and intensity ranges for the 20-
membered sulfamate ester library are presented.
Figure 3. Schematics of the Sterimol parameter system, describing the
subparameters B1 (minimum radius), B5 (maximum radius), and L
(length). Comparisons of nPr and CH2t-Bu demonstrate a deficiency
in the Sterimol parameters, where sterically distinct groups are
similarly described.
dimensional specificity to the description of steric bulk through
three subparameters: B1, substituent minimum radius; B5,
substituent maximum radius; and L, substituent length.
While the effectiveness of Sterimol parameters in various
contexts has been successfully demonstrated,9b,10a,11 this steric
descriptor still lacks information about the position along L at
which steric bulk resides. For example, as depicted in Figure 3,
Sterimol measures of the CH2t-Bu substituent are 1.52 (B1),
4.18 (B5), and 4.89 (L).15 Comparatively, the Sterimol system
describes nPr, a group with its own distinct apparent steric bulk,
as nearly isosteric with CH2t-Bu, measuring 1.52 (B1), 3.49
(B5), and 4.92 (L). A similar parameter deficiency occurs for
electronic description. The presence of R-group chlorine atoms,
particularly trichloromethyl, generally enhances selectivity (in
the absence of branching), independent of the chlorine atom
distance from the −NH2 group of the sulfamate moiety. This
observation cannot be explained through the use of the
ubiquitous electronic descriptor, pKa, or any descriptor of
induction.16 These apparent limitations warrant a more sophis-
ticated approach to characterize the underlying selectivity
trends in C−H amination. Thus, we have turned to IR molec-
ular vibrations, which were recently demonstrated as an
effective parameter for the development of free-energy type
relationships.10a Derived from the unique vibrational fingerprint
of every molecule and representative of the fundamental
energies, bond strengths, and dipole moments contained
therein, IR stretches were computationally calculated for each
sulfamate ester using M06−2X/TZVP.17
Figure 5. Plot of measured ΔΔG‡ versus Hammett σ+ for the DoE set
of sulfamate esters evaluated in the isoamylbenzene substrate series
R′ = OMe (1a), t-Bu (1c), H (1), Br (1d), CF3 (1b). ΔΔG‡ = −RT
ln(tertiary/benzylic), where T is 23 °C. Omitted from this plot are
data points corresponding to R = CH2CCl3, R′ = OMe (benzylic-to-
tertiary ratio >100:1) and R = CH(CH2Cl)2, R′ = Br (no measurable
products observed).
is responsible for benzylic versus tertiary amination ratios. Our
working hypothesis, for which we provide supporting evidence,
is that modifications to the nitrene precursor (i.e., sulfamate
ester) commensurately impact molecular properties of the
selectivity-defining transition states (vide infra).13 This is an im-
portant qualification, which allows ground state IR frequencies
and intensities to be computed for the simplest of these species,
the sulfamate ester. This approach significantly reduces the
computational effort, making the methodology tractable.
In order to proceed with free-energy relationship model
development, we identified a group of IR vibration parameters
as potential selectivity descriptors. From such a set, stepwise
linear regression analysis is performed, whereby the descriptors
While the reactive oxidant believed to be involved in the
selectivity-defining step of the Rh-catalyzed amination is a Rh-
nitrene (f, Figure 1b), our computed vibrational data are from
the sulfamate ester and not the nitrenoid. As noted above, the
differential energy between nitrenoid transition states (ΔΔG‡)
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Table 1. Training Set (Entries 1−23), External Validations (Entries 24−61), and Predictions (Entries 62−64, Bold)
pred.
meas.
ΔΔG‡
ΔΔG‡
entry
R
R′
4-H
(kcal/mol) (kcal/mol) meas. B/T
30 CH2CHCI2
31 (CH2)3CI
32 CH2t-Bu
33 CH2Cy
1.33
0.99
1.15
0.89
1.05
1.19
1.96
1.61
1.38
1.44
1.21
1.18
1.21
1.25
1.37
1.04
0.88
0.88
0.77
0.82
0.77
2.23
1.88
2.01
0.56
0.55
0.59
1.33
1.27
1.33
1.17
1.12
1.38
1.43
1.17
0.92
0.90
0.86
0.84
0.77
0.06
2.27
2.33
1.29
1.47
1.20
1.51
1.28
1.51
1.16
1.15
0.90
1.03
0.97
0.98
1.15
2.40
2.21
1.74
0.63
0.52
0.49
1.68
1.39
1.41
0.92
0.79
1.32
1.26
1.06
4.8 0.1
4.6 0.1
4.3 0.3
4.2 0.1
3.7 0.1
1.1 0.1
47.6 0.3
52.8 0.1
9.0 0.3
12.2 0.1
7.7 0.2
13.1 0.1
8.8 0.5
13.0 0.5
7.2 0.1
7.1 0.1
4.6 0.3
5.8 0.2
5.2 0.2
5.3 0.4
7.1 0.3
59.3 0.4
42.7 0.5
19.3 0.5
2.9 0.2
2.4 0.1
2.3 0.1
17.3 0.2
10.7 0.2
10.9 0.4
4.8 0.1
3.8 0.2
9.5 0.2
8.5 0.1
6.1 0.1
4-H
4-H
4-H
34 nBu
4-H
pred.
meas.
35 CH(CF3)2
36 CH2CCI3
37 CH2CF3
38 nPr
4-H
ΔΔG‡
ΔΔG‡
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
4-Br
entry
R
R′
(kcal/mol) (kcal/mol) meas. B/T
1
2
3
4
5
6
7
8
9
CH2CF3
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-H
2.32
2.02
2.15
1.77
1.82
1.70
1.86
1.58
1.25
1.06
1.09
0.92
0.86
0.96
0.95
0.70
0.41
0.31
0.26
0.27
0.11
0.39
0.24
1.05
1.02
1.07
0.87
1.02
1.01
2.61
2.03
2.15
1.72
1.95
1.81
1.94
1.29
1.18
0.98
0.86
0.72
0.61
0.84
0.89
0.83
0.49
0.41
0.41
0.31
0.06
0.46
0.46
1.29
1.15
1.15
1.04
1.03
1.01
85.0 1.4
31.6 0.1
38.9 0.9
18.6 0.3
27.7 1.3
21.5 0.5
26.9 0.5
8.9 0.1
7.4 0.2
5.3 0.3
4.3 0.1
3.4 0.2
2.8 0.1
4.2 0.3
4.5 0.1
4.1 0.3
2.3 0.1
2.0 0.2
2.0 0.1
1.7 0.1
1.1 0.1
2.2 0.1
2.2 0.2
9.0 0.3
7.0 0.3
7.0 0.1
5.9 0.1
5.8 0.1
5.6 0.3
nPr
39 (CH2)2CI
40 (CH2)2t-Bu
41 CH(CH2CI)2
42 CH2iPr
(CH2)2CI
(CH2)2t-Bu
CH(CH2CI)2
CH2iPr
43 (CH2)4CI
44 CH2CCI3
45 CH2CF3
46 nPr
(CH2)4CI
CH2CCl3
CH2CF3
4-Br
4-H
4-Br
10 nPr
4-H
47 (CH2)2CI
48 (CH2)2t-Bu
49 CH2iPr
4-Br
11 (CH2)2CI
12 (CH2)2t-Bu
13 CH(CH2CI)2
14 CH2iPr
4-H
4-Br
4-H
4-Br
4-H
50 (CH2)4CI
51 CH2CHCI2
52 (CH2)3CI
53 nBu
4-Br
4-H
4-OMe
4-OMe
4-OMe
3-CI
15 (CH2)4CI
16 CH2CCI3
17 CH2CF3
18 nPr
4-H
4-CF3
4-CF3
4-CF3
4-CF3
4-CF3
4-CF3
4-CF3
4-CF3
4-H
54 nBu
55 (CH2)2CI
56 CH2iPr
3-CI
19 (CH2)2CI
20 (CH2)2t-Bu
21 CH(CH2CI)2
22 CH2iPr
3-CI
57 (CH2)2CI
58 nBu
4-Ph
4-Ph
59 CH2CF3
60 (CH2)2CI
61 nBu
3-t-Bu
3-t-Bu
3-t-Bu
4-H
23 (CH2)4CI
24 (CH2)3CCI3
25 CH(Et)2
26 iPr
4-H
62 CH2CF2CF3
63 CH2(CF2)2CF3
4-H
4-H
27 Et
4-H
64 CH2C(Me)2CH2CI 4-H
28 (CH2)3CHCI2
29 Me
4-H
4-H
are statistically whittled down to a subset of parameters that
best mathematically relates features of the sulfamate ester to
ΔΔG‡ (equating to −RT ln(tertiary/benzylic), where R is the
ideal gas constant and T is temperature). As each sulfamate
ester is characterized with many disparate vibrational modes, we
chose those vibrations that were consistently identified in our
computations (i.e., major vibrational modes) and assumed to
significantly impact the Rh-nitrene selectivity profile. Given
these criteria, four vibrations were chosen as potential descrip-
tors of selectivity: O−S−N asymmetric stretch (νOSN), C−O
stretch (νCO), SO2 symmetric stretch (νSO2sym), and SO2
asymmetric stretch (νSO2asym). Figure 4 depicts a simulated IR
spectrum for sulfamate ester 2a (R = Me) and highlights both
the calculated frequencies and intensities of these four
vibrations, giving a total of eight vibration-derived descriptors
that were used for regression analysis.
systematically varied. Thus, eight sulfamate esters were selected
(termed the DoE set and noted with asterisks and bolded in
Figure 2) that quantitatively sample the observed range of B:T
ratios and qualitatively represent a distribution of steric and
electronic perturbations.
In addition to examining sulfamate substituent effects on B:T
selectivity, we have also varied the electronic structure of the
isoamylbenzene substrate. After preparing a traditional Hammett
series (R′ = OMe (1a), t-Bu (1c), H (1), Br (1d), CF3 (1c)),
this library was subjected to oxidation reactions with each of the
eight DoE-set sulfamate esters. (See Figure 5 for a description of
the two sets of experiments that did not yield measurable data.)
The selectivity results of this analysis are presented in Figure 5
and are correlated to Hammett σ+ values. As a measure of
resonance stabilization, Hammett σ+ values serve as a better
descriptor of the observed selectivity trends across varying R′
than do Hammett σ values.19 The higher degree of correlation
provided by σ+ values is consistent with the electrophilic nature
of the putative nitrenoid and developing δ+ charge at the car-
bon center undergoing oxidation in the transition structure.20
With data from reactions of the eight sulfamate esters (DoE
set) and three isoamylbenzene-derived substrates (R′ = OMe (1a),
Model Development. Prior to developing a mathematical
relationship between selectivity and the identified vibrational
frequencies and intensities, we first applied design of experiments
(DoE) principles to our initial 20-membered sulfamate ester
library (Figure 2).18 DoE tenants dictate that the most robust
mathematical models are developed from data sets that are
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Figure 6. (a) Normalized mathematical relationship, derived from
tabulated training set in Table 1, describing differential free energy of
benzylic (B)-to-tertiary (T) amination. R: ideal gas constant, T: 23 °C.
(b) Predicted versus measured ΔΔG‡ plot of training set and external
validations. Grayed data point, designated as an outlier, represents R =
CH(CF3)2, R′ = H. (c) Leave-one-out (LOO) analysis.
Figure 7. (a) Representation of increasing C−O stretch frequency
(νCO) versus sulfamate ester R group. (b) Representation of increasing
intensity of O−S−N asymmetric stretch (IOSN) versus sulfamate ester
R group. Grayed columns highlight model-informed predictions 2u
(R = CH2CF2CF3) and 2v (R = CH2(CF2)2CF3).
isoamylbenzene (1). The robustness of the model for describing
substrate variation was evaluated with five isoamylbenzene
derivatives: 1-t-Bu-4-isopentylbenzene (1c), 1-bromo-4-isopen-
tylbenzene (1d), 1-Cl-3-isoamylbenzene (1e), 1-Ph-4-isoamyl-
benzene (1f), and 1-t-Bu-3-isoamylbenzene (1g). The complete
external validation set is tabulated in Table 1. Graph-
ical representation of this data (red squares, Figure 6b) demon-
strates the overall good agreement between predicted ΔΔG‡
values and experimental measurements.
H (1), CF3(1b)), we subjected the 23-membered training set
(Table 1, see Figure 5 for an explanation of the data point
omitted) to a standard stepwise linear regression algorithm
(see Supporting Information for details).21 Using this algo-
rithm, which facilitates statistical exploration of the relationship
between vibrational parameters, σ+, and ΔΔG‡, the equation
depicted in Figure 6a can be formulated. To evaluate the accu-
racy of this model, we compare predicted and measured ΔΔG‡
in Figure 6b, which demonstrates a high level of correlation
between experimental values and model predictions. Leave-one-
out (LOO) analysis was also performed to evaluate the robustness
of the model (Figure 6c).22 The slope and R2 values, which are
close to unity, are positive indicators of the model’s accuracy.
External Validation of the Model. A third measure of
model strength was determined by externally validating the
model with data points not part of the training set. Of
the original 20-membered library, 12 sulfamate esters, which
were not members of the DoE set, were evaluated with
An obvious outlier between predicted and measured ΔΔG‡
values occurs with sulfamate ester 2n, (CF3)2CHOSO2NH2.
We hypothesize that this highly electron-deficient, sterically
large sulfamate ester may be forced to adopt conformations
not accessible to other nitrene sources in the defining C−N
bond forming event. It is also possible that 2n facilitates C−H
amination through a mechanistic pathway that differs from that
of other sulfamate esters. Future investigations of reactions with
2n are warranted; use of this reagent was discontinued for the
remainder of this study.
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Figure 8. (a) Plot of predicted versus measured ΔΔG‡ for amination of isoamylbenzene, 1. A mathematical model correlating differential reaction free
energy (ΔΔG‡) with IR vibrational data and Hammett σ+ parameters informed the design of new sulfamate esters. Sulfamate ester 2u affords the highest
B:T selectivity reported, to date, for Rh-catalyzed amination of isoamylbenzene. (b) Preparative scale (0.5 mmol) reactions using sulfamate ester 2u.
Analysis of the Model. We have capitalized on the
robustness of our model, which relies on both vibrational data
and substrate σ+ parameters, to predict new sulfamate struc-
tures that display a higher propensity toward benzylic C−H
insertion. As the relationship in Figure 6a is a normalized
equation, the magnitude of the coefficients yield information
about the relative influence of each parameter on selectivity.
Notably, the overriding selectivity determinant, σ+, is associated
with the strength of the benzylic C−H bond (vide supra).
Perhaps unsurprisingly, the C−O frequency (νCO) of the sul-
famate ester also plays a prominent role in this model. Included
as a single term and, again, within a cross-term, νCO is the
shortest conduit from the O-alkyl substituent to the sulfamate
moiety. The vibrational frequency of the C−O bond will reflect
changes in the substituent groups on the alkyl chain, which alter
the force constant and/or reduced mass (components of
vibrational modes).
It is particularly intriguing to find that the C−O stretching
vibration is coupled with the Hammett descriptor, σ+, in the
optimized selectivity model. This result suggests a synergistic
relationship between the nitrenoid and the isoamylbenzene
substrate, indicative of a defined intermolecular interaction
between these two species. While the precise nature of this
interaction is unclear, we considered illuminating the origin of
νCO trends by assessing sulfamate esters according to increasing
C−O frequency (Figure 7a). Qualitatively, we observed that the
more halogenated sulfamate esters showed greater νCO values.
In accordance with this trend, more polarized bonds vibrate
with energetically higher frequencies. Greater differential elec-
tronegativity across a bond increases the bond force constant
and, thus, its vibrational frequency.23
our use of the developed model as a tool for predicting new
sulfamate esters that yield improved B:T ratios.
Application of the Model. We have computationally
evaluated several sulfamate derivatives that included electro-
negative atoms and variation in chain-length; most of these,
however, were not predicted to afford improved site selection.
In contrast, sulfamate esters 2u (R = CH2CF2CF3) and 2v (R =
CH2(CF2)2CF3) were identified using our model, as these two
reagents were expected to give enhanced levels of the benzylic
oxidation product. In practice, the predicted selectivities closely
matched those measured, with sulfamate ester 2u effecting the
highest degree of site-selection observed for amination of
isoamylbenzene (1) (Figure 8a). The enhancement of selectivity
achieved by changing the sulfamate from Cl3CCH2OSO2NH3
(2k) to CF3CF2CH2OSO2NH2 (2u), albeit modest, is striking
given the apparent electronic similarities and steric differences
between these two reagents.
The identification of 2u and 2v by consideration of both νCO
and IOSN (gray columns, Figure 7) highlights the predictive
utility of our model. Of note, the calculated IR frequencies and
intensities of these nitrene sources do not represent the highest
observed values in the sulfamate ester library. This is ratio-
nalized by considering the interdependency of the terms
derived from vibrational modes, since these are intrinsically
linked. Thus, maximizing the value of νCO alone does not guar-
antee proportionate increases in ΔΔG‡ values. This under-
scores the balance that is achieved in the developed model (see
equation in Figure 6a) between the selectivity-enhancing effects
of the νCO and IOSN parameters (positive coefficients) and the
potentially deleterious effect on site selection of the (νCO)(σ+)
cross term (negative coefficient).
As a final step, we have evaluated the performance of sul-
famate ester 2u on a preparative scale (0.5 mmol) with iso-
amylbenzene (1). The benzylic product from this reaction was
obtained in 58% yield with the same level of B:T site-selectivity
(9.4:1) that was noted in the original evaluation process
(0.3 mmol scale). The reaction of 2u with substrate 5 shows
even higher levels of site selectivity in favor of the benzylic
amine product (60% yield). Finally, oxidation of a more
Patterning in a similar manner our analysis of the other
vibration-related parameter, IOSN, revealed in our model, we
constructed Figure 7b, which displays sulfamate ester R groups
according to increasing O−S−N asymmetric stretch intensities.
Organizing the data in this manner, we observe that variation in
IOSN is primarily characterized by increases in distal steric bulk
and by halogenation. These qualitative trends served to inform
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Journal of the American Chemical Society
Article
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yield.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data for new
substances, mathematical modeling details. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Author
sigman@chem.utah.edu; jdubois@stanford.edu
■
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B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M. L. X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
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Present Address
§Department of Chemistry, Duke University 3236 French
Science Center, 124 Science Drive, Durham, North Carolina
27708, United States.
Author Contributions
∥E. N. Bess and R. J. DeLuca contributed equally.
Notes
The authors declare no competing financial interest.
̈
ACKNOWLEDGMENTS
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;
■
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,
Revision C.01; Gaussian, Inc.: Wallingford, CT, 2009. (b) Zhao, Y.;
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This work was supported by NSF under the CCI Center for
Selective C−H Functionalization, CHE-1205646. This work
was also supported in the initial stages by NSF (CHE-
0749506). The support and resources from the Center for High
Performance Computing at the University of Utah are
gratefully acknowledged. J.L.R. was supported as a Ruth
Kirschstein NIH postdoctoral fellow (5F32GM089033) and
as a fellow of the Center for Molecular Analysis and Design
(CMAD) at Stanford.
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