Transition state analysis of an enantioselective Michael addition by a bifunctional thiourea organocatalyst

Article abstract of DOI:10.1039/c9ob00072k

The mechanism of the enantioselective Michael addition of diethyl malonate to trans-β-nitrostyrene catalyzed by a tertiary amine thiourea organocatalyst is explored using experimental ¹³C kinetic isotope effects and density functional theory calculations. Large primary ¹³C KIEs on the bond-forming carbon atoms of both reactants suggest that carbon-carbon bond formation is the rate-determining step in the catalytic cycle. This work resolves conflicting mechanistic pictures that have emerged from prior experimental and computational studies.

Full text of DOI:10.1039/c9ob00072k

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DOI: 10.1039/C9OB00072K
Journal Name
ARTICLE
Transition State Analysis of an Enantioselective Michael Addition
by a Bifunctional Thiourea Organocatalyst
†
Joseph A. Izzo, Yaroslaw Myshchuk, Jennifer S. Hirschi,* and Mathew J. Vetticatt*
WonReceived 00th January 20xx,
Accepted 00th January 20xx
The mechanism of the enantioselective Michael Addition of diethyl malonate to trans-β-nitrostyrene catalyzed by a
tertiary amine thiourea organocatalyst is explored using experimental 13C kinetic isotope effects and density functional
theory calculations. Large primary 13C KIEs on the bond-forming carbon atoms of both reactants suggest that carbon-
carbon bond formation is the rate-determining step in the catalytic cycle. This work resolves conflicting mechanistic
pictures that have emerged from prior experimental and computational studies.
DOI: 10.1039/x0xx00000x
www.rsc.org/
the tertiary amine moiety of
enolate complex
. The protonated chiral catalyst 3H+ directs
the addition of enolate to the si-face of TS2) resulting in
protonated catalyst nitronate complex . Proton transfer from
3H+ to the nitronate (TS3) yields product
and regenerates the
catalyst . Kinetic studies by Takemoto and co-workers show
that the reaction is first order in 1a 2a and – strongly
3 resulting in protonated catalyst-
Introduction
In 2003, Takemoto and co-workers introduced chiral
bifunctional thioureas as a powerful class of organocatalysts for
5
2
(
6
4
the enantioselective addition of malonates (
).1 Since this initial report, the tertiary amine thiourea catalyst
has been used in a diverse array of enantioselective
1) to nitro olefins
3
(2
,
3
3
supporting TS2 as the rate-determining step in the catalytic
transformations including the aza-Henry reaction,2 dynamic
kinetic resolution of aza-lactones,3 Michael addition to α,β-
unsaturated imides,4 the aldol reaction,5 sp2-alkylations,6 and
spiro-ketal formation7 as some important examples.
CF3
ROOC
R'
COOR
NO2
S
F3C
N
N
O
O
4
H
H
Additionally, success of the Takemoto catalyst (3) has inspired
the design and development of several new chiral scaffolds
involving variation of the groups that flank the thiourea
N
3
TS3
proton transfer
Me
RO
Me
OR
1
TS1
proton transfer
O
O
3H+
OR
CF3
RO
O
O
3H+
OR
S
R'
RO
F3C
N
H
N
N
5
2
H
O
O
O
O
N
3
ROOC
R'
COOR
NO2
Me
Me
O
O
6
OR
3H+
NO2
NO2
+
R'
R'
RO
R'
10 mol%
toluene, RT
RO
OR
1
2
4
N
2a R'=Ph
2b R'=H
4a R=Et R'=Ph
4b R=Me R'=H
O
O
1a R=Et
1b R=Me
TS2
C-C bond formation
Scheme 1. Enantioselective Michael addition of nitro olefins to malonates
catalyzed by bifunctional thiourea 3.
moiety.8
Over the past decade, the dual substrate mode of activation –
– simultaneous activation of both reacting partners – has
emerged as one of the mainstays of asymmetric
organocatalysis.9 The proposed mechanism for the Michael
Scheme 2. Catalytic cycle for bifunctional thiourea catalyzed Michael Addition
cycle.10
Takemoto’s experimental studies were followed by two
conflicting computational studies investigating the origin of
enantioselectivity and identity of the rate-determining step.11
A
theoretical study by Liu and co-workers, utilized DFT
calculations on the Michael addition of dimethylmalonate (1b
to 1-nitropropene (2b) using a truncated model of (the
aromatic moiety replaced by a hydrogen atom) as the model
)
addition of 1 to 2 begins with initial deprotonation of 1 (TS1) by
3
a.Department of Chemistry, Binghamton University, Binghamton, NY 13902, USA
*vetticatt@binghamton.edu
*jhirschi@binghamton.edu
system to compute the energetics of the reaction coordinate.11a
This study concludes that proton transfer from 3H+ to the
nitronate carbon (TS3) is the rate-determining step in the
catalytic cycle. Even though competing protonation of the
nitronate oxygen was calculated as a lower energy pathway, the
authors claim that the barrier for the tautomerization step (the
† Current address: Department of Chemistry, University at Buffalo, The State
University of New York, Buffalo, NY 14260 .
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x

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product resulting from proton transfer from O to C in the Michael addition to diketoesters (Zhong model Fig 1).13 This
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DOI: 10.1039/C9OB00072K
product nitronate) is too high in energy to make this pathway mode is similar to binding mode B but with an additional
accessible. Pápai and co-workers investigated the organization hydrogen bond to the achiral aryl group. This binding mode has
of the carbon-carbon bond-forming TS2 using 1b and 2a as been proposed in 1,3-dipolar cycloadditions as well.14 In
model reactants and unmodified catalyst 3 11b
This study another example, two additional binding modes were proposed
.
identified two viable binding modes for TS2 (Fig 1). In binding by Wong and co-workers for a related squaramide system
mode A, 2a is H-bonded to the thiourea moiety and the enolate (Wong and Wong’).15 In addition, several NMR, crystallographic,
of 1b is H-bonded to the protonated tertiary amine; conversely, and computational studies on similar systems have proposed
binding mode B corresponds to structures with the enolate of that the lowest energy binding conformation of the catalyst
1b is H-bonded to the thiourea moiety and 2a is H-bonded to adopts a “syn,anti” configuration of the thiourea functional
the protonated tertiary amine. Pápai calculated binding mode B group and not the traditional thiourea “anti,anti” configuration.
as energetically favored by 2.7 kcal/mol (E+zpe). The TS for An example of catalysis by this unique binding mode was
initial deprotonation of 1a (TS1) was calculated as lower in proposed by Schreiner for the binding of benzoic acid to the
energy by 2.9 kcal/mol than the lowest energy transition thiourea catalyst (Fig 1).16
structure located for TS2. Based on these observations, Pápai
proposed that carbon-carbon bond formation is the rate-
determining step.
Since the initial proposal of the two classic binding modes A and
B by Papai, transition state models with subtle variations have
been explored by several theoretical studies.12 For example, a
binding mode was proposed by Zhong and co-workers for the
Considering the broad interest in the title reaction (700+
citations for Takemoto’s original report) and the widespread
use of tertiary amine thioureas as asymmetric organocatalysts,
we decided to study the Michael addition of 1a to 2a catalyzed
by thiourea
3 using experimental kinetic isotope effects (KIEs)
and theoretical studies. Experimental KIEs probe the rate-
determining step of a reaction, and in conjunction with theory,
provide valuable insight into the transition state geometry of
this isotope sensitive step. We report herein the results of our
study which confirms rate-determining C-C bond formation
S
H
S
H
Ar'
N
H
N
H
Ar'
N
H
N
H
NMe2
H
NMe2
O d
d
O
Od
O
O
Od
O
H
(TS2) as the mechanism of this transformation. Comprehensive
N
N
OR
O
RO
DFT exploration of the various binding modes shown in Figure
1, along with predicted KIEs that match experimental
measurements, confirms that C-C bond-formation occurs via
binding mode B. The results presented here provide the first
“experimental picture” of the transition state of this seminal
reaction in bifunctional thiourea catalysis.
RO
Ar
OR
Ar
Binding Mode B (BMB)
Binding Mode A (BMA)
S
S
S
H
H
H
R'
R'
R'
N
R
N
N
N
H
N
H
N
H
R'
R'
Results and discussion
syn,syn
syn,anti
anti,anti
A. Experimental Kinetic Isotope Effects
CF3
The prototypical reaction of 1a and 2a catalyzed by
3 was
S
H
H
S
chosen for our mechanistic study. The KIEs for all carbon atoms
of 1a and 2a were simultaneously determined using NMR
methodology at natural abundance from starting material
analysis.17 Using a slightly modified version of Takemoto’s
H
F3C
N
H
N
N
N
H
Me
Me
N
H
N
H
H
F3C
N
H
O
O
O
CF3
H3
C
H
O
O
MeO
procedure (1a:2a of 1.25:1 instead of 2:1), reactions were taken
N
CH3
to ~80% conversion in 2a (and ~ 65% in 1a) as determined by
proton NMR analysis. Unreacted 1a and 2a were then reisolated
from the reaction mixture and the 13C isotopic composition was
compared to samples of 1a and 2a, not subjected to reaction
conditions. From the fractional conversions and the isotopic
enhancements, 13C KIEs were calculated using standard
methodology (Fig 2).18
O
Ph
O
Schreiner
Zhong
N
N
CF3
CF3
O
N
O
O
O
MeO
MeO
N
N
N
N
N
CF3
CF3
H
H
H
H
H
H
Observation of a significant primary (~3%) 13C KIE on C1 of 1a
and C1’ of 2a (Fig 2) suggests that both C1 and C1’ are involved
in the rate-determining transition state. The qualitative
interpretation of these measurements is that carbon-carbon
bond formation (TS2) is the first irreversible step of the catalytic
cycle – an interpretation that is consistent with earlier studies
O
S
S
O
Ph
Ph
Ph
Ph
Ph
Ph
Wong
Wong'
Figure 1. Reported binding modes for the bifunctional thiourea catalysis in various
reactions reported in the literature.
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by Takemoto and Pápai.10, 11b This interpretation is, however, Simulations were initiated from several of the lowest energy
View Article Online
18
inconsistent with rate-determining C-protonation of the binding modes for both the major andDmOiIn: 1o0r.10e3n9a/Cnt9iOoBm0e00rs7.2K
nitronate (TS3 - the Liu proposal10a) since such a step would Starting from the geometry of the lowest energy structures
exhibit a primary 13C KIE on C2’ of 2a and negligible 13C KIEs on derived from these conformational dynamics, transition
C1 of 1a and C1’ of 2a
.
structures were located in Gaussian using B3LYP/6-31+G** PCM
(toluene). Despite these extensive explorations of the reaction
space, TS2BMB-S was still found to be the lowest energy transition
structure leading to the major enantiomer. The lowest energy
1.029 (2)
1.029 (4)
0.993 (1)
0.997 (2)
1.001 (2)
1.008 (2)
O
O
transition structure leading to the minor enantiomer (TS2BMB-R
)
2'
NO2
1
2
was 2.4 kcal/mol higher in energy than TS2BMB-s. This
corresponds to a predicted ee of 97% (S), a result that is
consistent with the 93% ee (S) observed for this reaction. Our
extensive explorations led to the identification of an additional
minor enantiomer transition structure TS2Wong-R, corresponding
to the binding mode proposed by Wong and co-workers. This
transition structure was calculated to be 3.3 kcal/mol higher in
energy than TS2BMB-S (0.9 kcal/mol higher in energy than TS2BMB-
R). Finally, the second lowest energy transition structure leading
to the major enantiomer was TS2BMA-S, which was found to be
4.7 kcal/mol higher in energy that TS2BMB-S. This result provides
strong support that the reaction likely proceeds via binding
mode B. Structures found using alternative binding modes and
those located from dynamic simulations that are higher in
energy than the structures in Figure 3 are included in the
Supporting Information.
1'
O
Me
O
Me
1.000
(assumed) 0.994 (3)
1.006 (3)
1.034 (3)
1.030 (5)
0.999 (3)
0.999 (7)
1.000
(assumed)
Figure 2. Experimentally measured KIEs for the enantioselective Michael addition of 2a
to 1a catalyzed by 3.
B. Theoretical Structures
A quantitative interpretation of our experimental KIEs involved
the DFT calculations of transition structures for each step in the
catalytic cycle for the reaction of 1a and 2a catalyzed by 3. The
full system (89 atoms) was computed using the B3LYP method
and a 6-31+G** basis set.19 A polarizable continuum model
(PCM) for toluene, as implemented in Gaussian09, was
employed to account for the effects of the reaction solvent.20
This methodology is well supported in the literature and has
been shown to accurately describe the energetics of other
bifunctional thiourea-catalyzed reactions.21 To evaluate the
relative energetics of the transition structures leading to the
two enantiomers, single point energies were obtained using
B3LYLP-D3(BJ)/6-311++G** PCM (toluene).22 The computed
relative free energies (ΔΔG‡) are extrapolated Gibbs free
energies obtained by adding the free energy correction from
the B3LYP/6-31+G** PCM (toluene) optimization to the high-
level single point energy calculation. This is the first theoretical
study, performed at a high level of theory, on the full system
originally reported by Takemoto. Such a thorough theoretical
study is expected to provide highly precise KIE predictions for
comparison with experiment. A rigorous exploration for the
lowest energy structure for C-C bond formation (TS2), the
enantioselectivity determining step, was performed using DFT
calculations based upon existing models in the literature (Fig 1)
as well as a conformational search using quantum mechanical
simulations as implemented in DFTB+ as detailed below.23
The four lowest energy structures from our thorough
explorations are shown in Fig 3 along with their relative free
energies (ΔΔG‡). An initial search based on the binding modes
previously reported in the literature, resulted in the lowest
energy transition structure akin to binding mode B – TS2BMB-S
leading to the major enantiomer and TS2BMB-R for the minor
enantiomer of product (Fig 3). Additionally, a comprehensive
search of transition structures for TS2 was carried out by
modifying (a) the H-bonding contacts, (b) anti vs syn
conformation of the thiourea, and (c) position of the substrates
with regard to the bifunctional thiourea. To further ensure that
we had explored the large conformational space involved in the
system, a thorough search was conducted using the quantum
mechanical method DFTB+ with the Slater-Koster parameters.24
The origin of catalysis for the bifunctional thiourea catalyzed
Michael addition can be understood by examining the
interactions between the catalyst-substrate complex. At the
transition state for C-C bond formation, the greatest build-up of
negative charge is on the oxygen atoms of the nitro group of 2a
.
Interactions from the catalyst that stabilize this electron sink
should have the greatest effect in lowering the energy of the
transition state. Catalyst 3 possesses H-bonding sites at the two
thioamide thiourea moieties as well as the protonated tertiary
amine – the strongest H-bonding donor. Structures which
optimize these interactions are the most favored; additional
stability can arise from non-conventional H-bonding
interactions between the acidic aromatic hydrogens next to the
CF3 groups of the catalyst, as well as CHO interactions from the
methyl groups of the protonated tertiary amine. Transition
structure TS2BMB-S is stabilized by an H-bond (1.70 Å) between
the protonated tertiary amine and the negatively charged
oxygen of the nitro group of 2a. The nucleophilic malonate is
stabilized by H-bonds from the thioamide hydrogens of 3 to the
oxygen atoms of 1a (1.89 Å, 1.87 Å). In addition, one Ar-H bond
(2.52 Å) contributes to malonate stabilization. Similar
interactions are found in the Binding Mode B minor isomer
TS2BMB-R, the nitro group of 2a is stabilized solely by an H-bond
to the protonated amine (1.72 Å), and the malonates are
stabilized by H-bonds to the amides of the thiourea (1.82 Å, 1.87
Å). In TS2BMA-S the H-bonding partners are flipped, the
protonated amine of the catalyst stabilizes the malonate and
the thioamide hydrogens stabilize the nitro moiety. The higher
energy of transition structures in binding mode A indicates that
this is a less energetically stable configuration for catalysis.
Finally, in TS2Wong-R the nitro group is stabilized by two H-bonds
(one thioamide 1.88 Å, one protonated amine 1.83 Å) and the
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malonate is stabilized by one amide H-bond (1.92 Å) and one compared to TS2BMB-S is the most likelyViewoArritgicilenOnlionef
DOI: 10.1039/C9OB00072K
CHO interaction (2.23 Å) with the slightly acidic methyl enantioselectivity in this reaction.
hydrogen of the protonated tertiary amine moiety.
The origin of enantioselectivity for this reaction can be of the catalytic cycle (TS1 and TS3, Scheme 2), deprotonation of
understood using the above interaction analysis. The transition 1a by
and protonation of product nitronate by 3H+
structure TS2BMB-S and TS2BMB-R, possess very similar H-bonding respectively. Transition structure TS1C-dep for the deprotonation
networks, though they differ by 2.4 kcal/mol. The difference in of the keto-form of 1a by the amine moiety of is lower in
We also located transition structures for the first and third steps
3
3
energy between R and S can best be explained by examining the energy by 1.5 kcal/mol (ΔΔG‡) than TS1O-dep, the transition state
geometry around the forming C-C bond. In order to for deprotonation of the enol form of 1a. As for TS3, transition
accommodate the stabilizing interactions with the catalyst, the structure TS3C-prot for the protonation at the nitronate carbon by
forming C-C bond in TS2BMB-S adopts a staggered conformation the protonated amine moiety of
3 is higher in energy by 17.9
of the substituents (dihedral angle of ~60° between the alkene kcal/mol (ΔΔG‡) than TS3O-prot, the transition structure for
of 2a and the ester groups of 1a); conversely, transition protonation at the nitronate oxygen. This suggests that the final
structure TS2BMB-R has a more eclipsed configuration for these protonation takes place at the nitronate oxygen.25 Our
groups (dihedral ~30°) as the C-C bond forms. The resulting experimental isotope effects indicate the ensuing
increased steric interactions between substrates in TS2BMB-R
Figure 3. Four lowest energy transition structures for the Michael reaction of 1a with 2 catalyzed by 3. TS2BMB-S is favoured by 3.1 kcal/mol, consistent with experiment.
Important H-bonding interactions are indicated with dotted lines and shown in Angstroms. The relative free energies
are shown in parentheses.
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tautomerization leading to the final C-protonated product is a result consistent with prior experimental studies VbieywTAartkicelemOnolitnoe
facile process, since no KIE is observed on C2’. 26
and computational studies by Pápai. 10, 11b
DOI: 10.1039/C9OB00072K
C Calculated KIEs
Conclusions
As a final step, quantitative interpretation of our experimental
KIEs, predicted 13C KIEs were obtained from the scaled
vibrational frequencies of the respective transition structures
using the program ISOEFF98.27 A Wigner tunneling correction
was applied to all predicted KIEs.28 The resulting 13C KIE
The combination of experimental 13C KIEs and theoretical
calculations presented herein provide strong evidence for rate-
determining C-C bond formation in the bifunctional thiourea
catalyzed enantioselective addition of diethylmalonate to trans-
β-nitrostyrene. Our results provide the first “experimental”
picture of the key enantioselectivity-determining transition
state of this seminal reaction in bifunctional thiourea
organocatalysis.
predictions at the key carbon atoms of 1a and 2a for TS1
and TS3 along with comparison to corresponding
experimental values are presented in Table 1 .
, TS2,
a
Conflicts of interest
Transition
State
1-C
2-C
1’-C
2’-C
There are no conflicts to declare.
TS1C-dep
TS1O-dep
TS2BMB-S
TS3C-dep
TS3O-dep
Experimental
KIEs
1.011
1.001
1.032
0.994
0.996
1.005
1.010
1.007
0.999
1.000
N/A
N/A
1.031
1.000
1.000
N/A
N/A
0.999
1.015
0.993
Acknowledgement
1.030 (5)
1.034 (3)
1.008 (2) 1.029 (4) 0.999 (7)
1.001 (2) 1.029 (2) 0.999 (3)
Financial support for this work was provided by Binghamton
University startup funds and NIGMS (R01 GM126283). M.J.V.
J.S.H and J.A.I. acknowledge support from the National Science
Foundation through XSEDE resources provided by the XSEDE
Science Gateways Program.
Table 1. Predicted 13C KIEs for the key carbon atoms of 1a and 2a for all computed
transition structures and comparison to corresponding experimental KIEs.
The interpretation of the comparison of experimental and
theoretical KIEs is unambiguous. The predicted KIEs for lowest
energy carbon-carbon bond-forming transition state (TS2BMB-S
)
Notes and references
are in excellent agreement with the experimental KIEs for the
bond-forming carbon atoms of both 1a (1.032 on C1) and 2a
(1.031 on C1’). This provides strong evidence for a mechanism
involving rate-determining carbon-carbon bond formation – a
Experimental procedures, theoretical methodology, and
coordinates of all calculated structures and product
characterization data. This material is included in the
Supporting Information.
1
T
. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc., 2003, 125, 1310. (d) T. J. Auvil, A. G. Schafer, A. E. Mattson, European J. Org.
12672–12673.
Chem. 2014, 2633–2646.
9
2 T. Okino, S. Nakamura, T. Furukawa, Y. Takemoto, Org. Lett. 2004,
6, 625–627.
Science of Synthesis: Asymmetric Organocatalysis II; List, B.,
Maruoka, K., Eds.; Thieme: Stuttgart, Germany, 2012. pp 437. I’m not
sure how this Journal wants books cited.
3
A. Berkessel, F. Cleemann, S. Mukherjee, T. N. Müller, J. Lex,
Angew. Chemie - Int. Ed. 2005, 44, 807–811.
10 T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am. Chem.
Soc. 2005, 127, 119–125.
4 Y. Hoashi, T.Okino, Y. Takemoto, Angew. Chemie - Int. Ed. 2005, 44,
4032–4035.
11
(a) R. Zhu, D. Zhang, J. Wu, C. Liu, Tetrahedron Asymmetry 2006,
17, 1611–1616.; (b) A. Hamza, G. Schubert, T. Soós, I. Pápai J. Am.
Chem. Soc. 2006, 128, 13151–13160.
5
S. Sakamoto, N. Kazumi, Y. Kobayashi, C. Tsukano, Y. Takemoto,
Org. Lett. 2014, 16, 4758–4761.
12
A selection of computational papers that have investigated
6 M. S. Manna, S. Mukherjee, J. Am. Chem. Soc. 2015, 137, 130–133.
the binding modes on this and similar systems are listed here (a)
T. Azuma, Y. Kobayashi, K. Sakata, T. Sasamori, N. Tokitoh, Y.
Takemoto, J. Org. Chem. 2014, 79, 1805–1817. (b) A. Sengupta, R. B.
Sunoj, J. Org. Chem. 2012, 77, 10525–10536. (c) T. E. Shubina, M.
Freund, S. Schenker, T. Clark, S. B. Tsogoeva, Beilstein J. Org. Chem.
2012, 8, 1485–1498. (d) C. Trujillo, I. Rozas, A. Botte, S. J. Connon,
Chem. Commun. 2017, 53, 8874–8877. (e) A. Quintard, D.
Cheshmedzhieva, M. d. M. Sanchez Duque, A. Gaudel-Siri, J. V.
7 N. Yoneda, Y. Fukata, K. Asano, S. Matsubara, Angew. Chemie - Int.
Ed. 2015, 54, 15497–15500.
8
Selected examples include (a) Y. Takemoto, Org. Biomol. Chem.
2005, 3, 4299–4306. (b) Y. Takemoto, Chem. Pharm. Bull. 2010, 58,
593–601. (c) W. Y. Siau, J. Wang, Catal. Sci. Technol. 2011, 1, 1298–
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21 (a) S. J. Zuend, E. N. Jacobsen, J. Am. Chem. Soc. 2007, 129, 15872–
15883. (b) S. J. Zuend, E. N. Jacobsen, J. Am. Chem. SVoicew. 2A0rti0c9le,O1n3lin1e,
15358–15374. (c) H. Xu, S. J. Zuend, M. G. Woll, Y. Tao, E. N. Jacobsen,
Science 2010, 327, 986–990.
DOI: 10.1039/C9OB00072K
Naubron, Y. Génisson, J. C. Plaquevent, X. Bugaut, J. Rodriguez, T.
Constantieux, Chem. - A Eur. J. 2015, 21, 778–790. (f) X. Li, Y. Y. Zhang,
X. S. Xue, J. L. Jin, B. X. Tan, C. Liu, N. Dong, J. P. Cheng, European J.
Org. Chem. 2012, 2, 1774–1782. (g) M. N. Grayson, J. Org. Chem.
2017, 82, 4396–4401. (h) M. N. Grayson, K. N. Houk, J. Am. Chem.
Soc. 2016, 138, 9041–9044.
22 (a) S. Grimme, S. Ehrlich, L. Goerigk, J. Comput. Chem. 2011, 32,
1456–1465. (b) R. Krishnan, J. S. Binkley, R. Seeger, J. A. Pople, J.
Chem. Phys. 1980, 72, 650–654.
13
B. Tan, Y. Lu, X. Zeng, P. J. Chua, G. Zhong, Org. Lett. 2010, 12,
23 B. Aradi, B. Hourahine, T. Frauenheim, J. Phys. Chem. A 2007, 111,
5678–5684.
2682–2685.
14
F. Esteban, W. Cieślik, E. M. Arpa, A. Guerrero-Corella, S. Díaz-
24
(a) M. Elstner, D. Porezag, G. Jungnickel, J. Elsner, M. Haugk, T.
Tendero, J. Perles, J. A. Fernández-Salas, A. Fraile, J. Alemán, ACS
Catal. 2018, 8, 1884–1890.
Frauenheim, S. Suhai, G. Seifert, Phys. Rev. B 1998, 58, 7260–7268.
(b) J. C. Slater, G. F. Koster, Phys. Rev. 1954, 94, 1498–1524. (c) D. A.
Papaconstantopoulos, Handbook of the Band Structure of Elemental
Solids; Plenum Press: New York, 1986.
15 J. Guo, M. W. Wong, J. Org. Chem. 2017, 82, 4362–4368.
16 (a) Z. Zhang, K. M. Lippert, H. Hausmann, M. Kotke, P. R. Schreiner,
J. Org. Chem. 2011, 76, 9764–9776. (b) A. Supady, S. Hecht, C.
Baldauf, Org. Lett. 2017, 19, 4199–4202. (c) N. Hayama, R. Kuramoto,
T. Földes, K. Nishibayashi, Y. Kobayashi, I. Pápai, Y. Takemoto, J. Am.
Chem. Soc. 2018, 140, 12216-12225. (d) M. Heshmat, J. Phys. Chem.
A 2018, 122, 7974-7982. (e) Á. Madarász, Z. Dósa, S. Varga, T. Soós,
A. Csámpai, I. Pápai, ACS Catal. 2016, 6, 4379–4387. (f) G. Tárkányi,
P. Király, T. Soós, S. Varga, Chem. - A Eur. J. 2012, 18, 1918–1922.
25 Calculational details and cartesian coordinates for TS1 and TS3 are
included in the Supporting Information.
26 We were unable to locate a tautomerization transition structure
for TS3O-prot that was lower in energy than C-C bond formation. TS3O-
may be reversible and final protonation occurs at the carbon
prot
(TS3C-prot), though the energy for this transition structure is also
higher than C-C bond formation. However, the most likely scenario is
that DFT fails to correctly predict the energies of proton transfers
with respect to C-C bond formation. See Plata, R. E.; Singleton, D.A.
J. Am. Chem. Soc. 2015, 137, 3811-3826. A detailed discussion on the
energetics of the given Michael reaction as well as the limitations of
DFT calculations in predicting relative energies of transition
structures with and without proton transfers is included in the
Supporting Information (S17).
17 D. A. Singleton, A. A. Thomas, J. Am. Chem. Soc. 1995, 117, 9357–
9358.
18 See supporting information for details.
19 (a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652. (b) C. Lee, W.
Yang, R. G. Parr, Phys. Rev. B 1998, 37, 785–789. (c) P. J. Stephens, F.
J. Devlin, C. F. Chabalowski, M. J. Frisch, J. Phys. Chem. 1994, 98,
11623–11627.; (d) P. C. Hariharan, J. A. Pople, Theor. Chim. Acta
1973, 213, 213–222.
27 V. Anisimov, P. Paneth, J. Math. Chem. 1999, 26, 75–86.
28 E. P. Wigner, Phys. Chem. 1932, B19, 203.
20
(a) C. Amovilli, V. Barone, R. Cammi, E. Cancès, M. Cossi, B.
Mennucci, C. S. Pomelli, J. Tomasi, J. Adv. Quantum Chem. 1998, 32,
227–261. (b) See supporting information for full Gaussian09 citaiton
6 | J. Name., 2012, 00, 1-3
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