Isotope Effects Reveal an Alternative Mechanism for "iminium-Ion" Catalysis

Article abstract of DOI:10.1021/jacs.8b04856

A novel mechanism for the epoxidation of enals with hydrogen peroxide catalyzed by diarylprolinol silyl ether supported by experimental ¹³C kinetic isotope effects (KIEs) and density functional theory calculations is presented. Normal ¹³

Full text of DOI:10.1021/jacs.8b04856

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Communication
Isotope Effects Reveal an Alternative Mechanism for ‘Iminium-Ion’ Catalysis
Joseph A Izzo, Pernille H. Poulsen, Jeremy A Intrator, Karl Anker Jørgensen, and Mathew J. Vetticatt
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b04856 • Publication Date (Web): 25 Jun 2018
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Isotope Effects Reveal an Alternative Mechanism for ‘Iminium-Ion’ Catalysis
Joseph A. Izzo, ‡ Pernille H. Poulsen, † Jeremy A. Intrator, ‡ Karl Anker Jørgensen,†* and Mathew J. Vetticatt ‡*
‡Department of Chemistry, Binghamton University, Binghamton, New York 13902
†Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
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RECEIVED DATE (automatically inserted by publisher); vetticatt@binghamton.edu
In 2005, the enantioselective epoxidation of enals 1
catalyzed by a diarylprolinol silyl ether catalyst 3a with
hydrogen peroxide 2a (as an oxidation agent) was developed
(Scheme 2).8 The epoxidation reaction, performed in the
absence of acid coꢀcatalyst or amine salts, was proposed to
proceed via transient formation of an iminiumꢀion
intermediate 8 followed by attack of 2a on the activated βꢀ
carbon (Scheme 2, outer catalytic cycle). The αꢀcarbon of
the resulting enamine intermediate 9.H+ functions as a
nucleophile to effect the ring closure and provide productꢀ
iminiumꢀion species 10. Subsequent hydrolysis regenerates
3a and delivers the epoxy aldehyde product 5. Kinetic
studies revealed that the reaction is autocatalytic when
performed in a biphasic dichloromethaneꢀwater mixture.9
This observation was rationalized as being a result of the
peroxyhydrate of the epoxy aldehyde 2a' functioning as a
‘phaseꢀtransfer’ nucleophile in the rateꢀdetermining βꢀ
functionalization step.
ABSTRACT: A novel mechanism for the epoxidation of
enals with hydrogen peroxide catalyzed by diarylprolinol
silyl ether supported by experimental 13C kinetic isotope
effects (KIEs) and density functional theory calculations is
presented. Normal 13C KIEs, measured on both the carbonylꢀ
and βꢀcarbon atoms of the enal, suggest participation of both
carbon atoms in the rateꢀdetermining step. Calculations
show that the widely accepted iminiumꢀion mechanism does
not account for this experimental observation. A synꢀSN2′
substitution mechanism, that avoids formation of a discrete
iminiumꢀion intermediate, emerges as the most likely
mechanism based on agreement between experimental and
predicted KIEs.
Enantioselective βꢀfunctionalization of α,βꢀunsaturated
aldehydes (enals, 1) using chiral primary or secondary
amines
3
is an important branch of asymmetric
,
organocatalysis known as iminiumꢀion catalysis.1 2 This
mode of catalysis is also referred to as ‘LUMOꢀlowering
catalysis’ since formation of a transient iminiumꢀion via
condensation of 1 and 3 lowers the energy of the LUMO and
facilitates nucleophilic attack at the βꢀcarbon atom (Scheme
1).3 Typical catalysts for this transformation are neutral
amines, amine salts, or neutral amines with an acid
additive.1,2,4 The iminiumꢀion intermediate has been isolated
and characterized in a number of reactions employing amine
salt catalysts.5 However, the intermediacy of the iminiumꢀ
ion has not been established in reactions conducted with
neutral amines as catalyst.6 Recent observations by Hayashi
et al. show that the presence versus absence of an acid coꢀ
catalyst can trigger different reaction pathways under
otherwise identical conditions.7 The results presented in this
communication provide the first experimental evidence for
an alternative mechanism in βꢀfunctionalization reactions
catalyzed by neutral amine catalysts.
Iminium-ion catalysis: LUMO-lowering via iminium-ion formation
O
H
H
– 3
NR'R"
H
OH
R
O
R1
R'R''NH
3
R
Y
Y
H
4
+
H
R1
Y
H
O
R
1
2
R1
H
– R1H
– 3
Y
Y = nucleophilic
center
nucleophile attack on
LUMO-lowered enal
5
R
Scheme 1. Organocatalytic reactions of enals facilitated via
iminiumꢀion catalysis
Scheme 2. Conflicting mechanisms for the organocatalytic
epoxidation of enals catalyzed by secondary amine
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Computational studies by Santos suggest that the role of
RDS (conversion of 6 to 7) does not involve C1 or C3. The
experimental KIEs are also inconsistent with the “classical”
iminiumꢀion mechanism, which involves only C3 in the
RDS. In fact, there is no single step in either catalytic cycle
that involves simultaneous bonding changes at C1 and C3.
Our experimental KIE results cannot be rationalized on the
basis of the current understanding of the reaction
mechanism. This necessitates an exploration of alternative
kinetic scenarios and/or reaction pathways that can account
for the KIE measurements.
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2
3
4
5
6
7
8
hydrogen peroxide 2a is as a coꢀcatalyst in multiple steps
involved in iminiumꢀion formation.10 Specifically, that 2a
acts as a proton shuttle in the conversion of 6 to 7, and as a
proton source that aids in the loss of hydroxide from 7 to
form 8 (Scheme 2, inner catalytic cycle). Additionally, the
authors assert the explicit involvement of a hydroxide ion to
activate 2a via deprotonation in the βꢀattack step (inner
catalytic cycle, 8 to 9). Based on the computed free energy
profiles, it was proposed that conversion of 6 to 7 is the rateꢀ
determining step (RDS) while conversion of 8 to 9 is the
selectivityꢀdetermining step.10
To obtain insight into the conflicting mechanistic picture
that emerges from these two studies, we decided to
investigate this reaction using a combination of experimental
13C kinetic isotope effects (KIEs) and density functional
theory calculations. We report herein, the results from these
studies which strongly support a novel mechanism that
proceeds via a concerted pathway (Scheme 2, pathway
highlighted in green) and renders the key iminiumꢀion as an
offꢀcycle intermediate in catalysis. We expect this
mechanism, proceeding via a synꢀSN2′ transition state (TS)
involving direct conversion of the carbinolamine
intermediate 7 to the βꢀsubstituted enamine intermediate 9,
to be relevant to other iminiumꢀion reactions – particularly
ones that utilize neutral amines as catalysts.
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Computational methods: We modeled the reaction of 1a
and 2a catalyzed by 3a (total 84 atoms) at the B3LYP/6ꢀ
,
31G* level of theory as implemented by Gaussian 09.13 14
Transition state (TS) structures were located for each step of
the catalytic cycle in order to generate a free energy profile
for the title reaction (see SI). A systematic conformational
search was performed by varying the orientation of the
chiral moiety of the catalyst, the pucker of the pyrrolidine
ring, and the orientation of the peroxide for each of the TSs
presented in the manuscript.15 The predicted 13C KIEs were
derived from the scaled vibrational frequencies using the
program ISOEFF98.16,17 An infinite parabola tunneling
correction was applied to all predicted KIEs.18 To evaluate
the relative energetics of competing pathways, single point
energies for the relevant TSs were obtained using B3LYPꢀ
D3(BJ)/6ꢀ311++G** SMD (water).19 The computed free
energy barriers (ꢀG‡) presented in the manuscript are
extrapolated Gibbs free energies obtained by adding the free
energy correction from the B3LYP/6ꢀ31G* optimization to
the highꢀlevel single point energy calculation. The ꢀG‡
values in the manuscript were further evaluated using single
point energy calculations performed using a total of 10 DFT
methods20 with both an SMD and PCM21 solvent model – all
methods gave identical trends in the relative ꢀG‡ for the TSs
Experimental
KIEs:
The
reaction
of
p-
chlorocinnamaldehyde 1a (1, R = p-ClC6H4) and hydrogen
peroxide 2a catalyzed by 3a was chosen for the
determination of experimental 13C KIEs at natural
abundance. Four identical reactions were taken to 72 ± 2%,
77 ± 2%, 68 ± 2%, and 61 ± 2% conversion (of 1a) as
determined by NMR analysis of the reaction mixture after a
reductive workup. The 13C isotopic composition of reꢀ
isolated 1a was compared to samples of 1a not subjected to
the reaction conditions.11 From the changes in relative
isotopic composition and the fractional conversion, 13C KIEs
were determined in a standard way.12 The experimental KIEs
for every position of 1a, as determined from a total of 25
such comparisons, are shown in Figure 1.
described herein.15
a) Iminium-ion formation and conjugate addition (AN') are
co-RDS
NR'R"
NR'R"
Iminium-ion
formation
OH
HO
OH
H
O
R
7
R
8
OH
O
H
AN'
b) Nucleophilic substitution – SN2'
NR'R"
SN2'
OH
NR'R"
H O
HO
+
2
O
H
H
R
O
R
7
O
9
H
Figure 1 Experimental KIEs for the 3a organocatalyzed
epoxidation reaction of 1a. Numbers in parenthesis represent
the 95% confidence range of each experimental KIE as
determined from 25 independent measurements.
Figure 2. Two possible mechanistic pathways that are
qualitatively consistent with experimental 13C KIEs. The atoms
highlighted in pink in the intermediates preceding the likely
rateꢀdetermining step indicate positions where a normal 13C KIE
is expected.
Qualitative interpretation of experimental KIEs: There is
a significant normal KIE (~2.5%) on the carbonylꢀcarbon
(C1) and a smaller, yet nonꢀunity KIE (~1.0 %) on the βꢀ
carbon (C3) of 1a (Figure 1). All other carbon atoms in the
molecule have nearꢀunity KIEs. The qualitative
interpretation of these experimental KIEs is that both carbon
atoms (C1 and C3) are involved in the first irreversible step
for 1a in the catalytic cycle. This interpretation is
inconsistent with the Santos mechanism10 since the proposed
Our computational investigation of Scheme 2 revealed
that all steps leading up to formation of the carbinolamine 7
along with all steps following formation of the enamine
peroxide intermediate 9/9.H+ are facile,15 and likely not rateꢀ
determining.22 Based on this finding and the qualitative
interpretation of our KIEs, two main possibilities emerge as
likely explanations: (i) formation of iminiumꢀion and the
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conjugate addition (AN′) of the nucleophile are coꢀrateꢀ
The significantly higher barrier for TS-AN′ relative to TS-
iminium suggests that these are likely not coꢀrateꢀ
determining steps. Furthermore, if TS-iminium and TS-AN′
are coꢀrateꢀdetermining, a weighted average of the predicted
13C KIEs for these TSs (based on their relative energies)
should be consistent with experiment. However, the
predicted 13C KIEs at C1 and C3 for both these TSs are
lower than the corresponding experimental KIEs (Figure 3)
suggesting that neither of these TSs nor any combination of
these TSs (regardless of the computed relative energies) can
account for the experimental 13C KIEs. Based on these
observations, we can eliminate co-rate-determining TS-
iminium and TS-AN′ as a viable mechanism for the
reaction.
2. Nucleophilic substitution mechanism: We then turned
our attention to the mechanism involving direct conversion
of 7 to 9 via an SN2′ transition state (TS-SN2′, Figure 4). TS-
SN2′ is characterized by a syn orientation of the nucleophile
(2a) and the leaving group.25 Additionally, there is a proton
transfer event from 2a to 7 that occurs concomitantly with
C1−O bondꢀcleavage and C3−O bondꢀformation. This
proton transfer serves two key purposes: (i) facilitates the
loss of hydroxide ion from 7 by making it a better leaving
group, and (ii) activates 2a for a concomitant nucleophilic
attack on 7.
1
2
3
4
5
6
7
8
determining steps in the catalytic cycle (Figure 2a). In this
scenario, the exact magnitude of the observed 13C KIEs at
the carbonylꢀ and the βꢀcarbon are a weighted average
(based on relative energies) of the predicted KIEs of these
two TSs,23 or (ii) formation of iminiumꢀion and the βꢀattack
occurs in a single irreversible step via an SN2′ TS resulting
in normal KIEs on both the carbonylꢀ and the βꢀcarbon
atoms (Figure 2b). Such a mechanism ꢀ that does not involve
the ‘iminiumꢀion’ intermediate in the key βꢀ
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functionalization step
ꢀ is without precedent in the
literature.24
1. Iminium-ion formation and conjugate addition are co-
rate-determining steps: We modeled the step involving
conversion of 7 to 8 mediated by a molecule of 2a as
suggested by Santos (Figure 3, TS-iminium).10 Examination
of this TS reveals that 2a catalyzes the formation of 8 by
protonating the hydroxide leaving group. The peroxide anion
formed is stabilized by two CH…Oꢀinteractions with the
moderately acidic CHs of the catalyst. Next, we identified
the TS for the hydroxide mediated conjugate addition of 2a
to 8 to form 9 (Figure 3, TS-AN′). In this TS, deprotonation
of 2a by hydroxide results in an ‘early’ TS (rCꢀO = 2.49 Å)
for the conjugate addition. All attempts to locate a TS
corresponding to attack of 2a without activation by
hydroxide (Scheme 2, 8 ꢀ 9.H+) were unsuccessful
suggesting that activation of 2a by deprotonation is a key
feature of the AN′ step.
The magnitude of the predicted 13C KIE at C1 and C3 for
TS-SN2′ is proportional to C−O bond order at these centers.
The higher bond order of the breaking C1−O (rC1ꢀO = 2.24
Å) results in a predicted KIE of 1.019 at C1 while the lower
C3−O bond order (rC3ꢀO = 2.43 Å) results in a predicted KIE
of 1.008 at C3. Both these predicted values are in excellent
agreement with experimental KIEs (Figure 4). Finally, the
computed ꢀG‡ for TS-SN2′ is 15.3 kcal/mol (versus 7); this
is 4.0 kcal/mol lower in energy relative to TS-AN′ – a result
that is consistent across all DFT methods explored.26 This
result, along with the excellent match of experimental and
predicted KIEs, lends strong support for this unprecedented
nucleophilic substitution mechanism for the βꢀ
functionalization of enals.
Figure 3. Transition structures for iminiumꢀion formation and
conjugate addition (AN′) steps, as proposed by Santos,
calculated for the reaction of 1a and 2a catalyzed by 3a. The
free energy barriers are computed relative to intermediate 7.
Predicted 13C KIEs for both transition structures are also shown.
The ꢀG‡ values for TS-iminium and TS-AN′ are 7.8 and
19.3 kcal/mol, respectively, with respect to intermediate 7.
Figure 4. Transition structure for the concerted pathway (7 to
9), calculated for the reaction of 1a and 2a catalyzed by 3a is
shown. The free energy barrier is computed relative to
intermediate 7. Predicted 13C KIEs for this transition structure
are also displayed.
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It must be noted that conversion of 7 to 8 via TS-iminium
1
occurs more rapidly than the conversion of 7 to 9 via TS-
SN2′. However, the higher barrier for TS-AN′ (relative to TS-
SN2′) forces 8 to revert to 7 and proceed via TS-SN2′. The
iminium-ion intermediate 8 is therefore proposed as an off-
cycle intermediate in the catalytic cycle. Finally, the reaction
selectivity was explored by calculating the synꢀSN2′
transition structure that delivers the opposite chirality at the
βꢀcarbon, TS-SN2′-ent (not shown) is 1.63 kcal/mol higher
in energy that TS-SN2′ – a difference that corresponds to
88% ee at room temperature. This is in reasonable
agreement with the 98% ee observed experimentally for this
reaction and lends support to TS-SN2′ as the
enantioselectivityꢀdetermining step.
In conclusion, the widely accepted conjugate addition
mechanism, termed as ‘iminium catalysis’, is not applicable
to the epoxidation of enals catalyzed by a neutral amine. An
SN2′ pathway is identified as the rateꢀ and enantioselectivity
determining step of this reaction. We expect this
unprecedented mechanism to be applicable to a wide range
of aminocatalytic βꢀfunctionalization reactions that are
currently assumed to proceed via an iminiumꢀion
intermediate.
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conditions as an intermediate in enamine catalysis by
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KIE experiments.
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Acknowledgement: Financial support for this work was
provided by Binghamton University startup funds and
NIGMS (R01 GM126283). M.J.V. and J.A.Iz. acknowledge
support from the National Science Foundation through
XSEDE resources provided by the XSEDE Science
Gateways Program. KAJ thanks Carlsberg Foundation's
‘Semper Ardens’ programme for financial support.
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15 See Supporting Information for detailed discussion of the
computational methods and results not included in the
manuscript.
16 Anisimov, V.; Paneth, P. J. Math. Chem. 1999, 26, 75.
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Author Information
Corresponding Authors
vetticatt@binghamton.edu
kaj@chem.au.dk
ORCID
Joseph A. Izzo 0000ꢀ0002ꢀ2875ꢀ2138
Karl Anker Jørgensen 0000ꢀ0002ꢀ3482ꢀ6236
Mathew J. Vetticatt 0000ꢀ0001ꢀ5709ꢀ0885
Supporting Information Available: Experimental procedures,
coordinates of all calculated structures and product
characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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20 The 10 methods used are B3LYPꢀD3(0), B3LYPꢀD3(BJ),
examples are listed here: (a) Stork, G.; White, W. N. J. Am.
Chem. Soc. 1956, 78, 4609–4619. (b) Stork, G.; Kreft, A. F.
I. J. Am. Chem. Soc. 1977, 99, 3850–3851. (c) Stork, G.;
Kreft, A. F. I. J. Am. Chem. Soc. 1977, 99, 3851–3853. (d)
Streitwieser, A.; Jayasree, E. G.; Hasanayn, F.; Leung, S. S.
J. Org. Chem. 2008, 73, 9426–9434. (e) Guthrie, R. D.
System for Symbolic Representation of Reaction
Mechanisms. Pure Appl. Chem. 1988, 61, 23–56 (and the
references therein). (f) Seebach, D.; Gilmour, R.; Grošelj, U.;
Deniau, G.; Sparr, C.; Ebert, M. O.; Beck, A. K.; McCusker,
L. B.; Šišak, D.; Uchimaru, T. Helv. Chim. Acta 2010, 93,
603–634 (appendix and the references therein).
M052xꢀD3(0), M062xꢀD3(0), M06LꢀD3(0), ωB97XD,
PBE0ꢀD3(BJ), mPW1K, MN15ꢀL (each with 6ꢀ311++G**
basis set), and ωB97XD/def2ꢀTZVPP.
21 Amovilli, C.; Barone, V.; Cammi, R.; Cancès, E.; Cossi, M.;
Mennucci, B.; Pomelli, C. S.; Tomasi, J. Adv. Quantum
Chem. 1998, 32, 227–261.
22 This is in variance with ref. 10, which concludes that
conversion of 6 to 7 is the RDS. We have performed
computations to evaluate this discrepancy and these results
are discussed in detail in the Supporting Information.
23 Selected examples where multiple transition states contribute
to KIEs see (a) Plata, R. E.; Singleton, D. A. J. Am. Chem.
Soc. 2015, 137, 3811ꢀ3826. (b) Villano, S. M.; Kato, S.;
Bierbaum, V. M. J. Am. Chem. Soc. 2006, 128, 736–737.
24 Other mechanistic pathways that are in qualitative agreement
with the KIEs were also explored but are omitted from the
manucript to avoid redundant discussions. See Supporting
Information for full details.
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26 The uncorrected ꢀG‡ values for TS-iminium, TS-AN′, and
TS-SN2′ are 18.3, 29.7, and 25.8 kcal/mol respectively, with
respect to the separated starting materials. See Supporting
Information for ꢀG‡ values calculated using 19 other DFT
methods. See ref. 23a for an important discussion on
interpretation of free energy barriers obtained from
computational studies.
25 The synꢀstereochemical course of the SN2′ reaction has been
extensively studied by Stork and others. Some important
novel SN2' substitution mechanism
NR'R"
OH
significant 13C KIE observed
O
O
H
O
H
NR'R"
H
R
O
R
H
NR'R"
OH
O
H
R
HOO
+
H2O
+
H2O2
R
R
+
+
NR'R"
NHR'R''
NHR'R''
(catalyst)
H
O
NR'R"
R
iminium ion is an
off-cycle
intermediate
O
H
widely accepted iminium ion
addition mechanism (AN'
R
)
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