Kinetics of iminium ion catalysis

Article abstract of DOI:10.1002/anie.200705539

Identifying the bottleneck: Kinetic and computational data for the key steps of the iminium ion catalyzed Diels-Alder reaction show that the cycloaddition (step II in scheme) is the rate-determining step of the catalytic cycle and provide a rationale for

Full text of DOI:10.1002/anie.200705539

Communications
DOI: 10.1002/anie.200705539
Organocatalysis
Kinetics of Iminium Ion Catalysis**
Gareth Evans, Timothy J. K. Gibbs, Robert L. Jenkins, Simon J. Coles, Michael B. Hursthouse,
James A. Platts,* and Nicholas C. O. Tomkinson*
Since MacMillanꢀs original report in 2000,[1a] iminium ion
catalysis using cyclic secondary amines has been established
as an effective platform for asymmetric Diels–Alder,[1]
conjugate addition,[2–6] [3+2] cycloaddition,[7] [4+3] cycload-
dition,[8] and conjugate reduction[9] reactions, thereby provid-
ing powerful new methods for fundamental bond-construc-
tion processes. Such reactions frequently proceed in high yield
and with exceptional levels of asymmetric induction, thus
forming a new mode of reactivity that has met with over-
whelming acceptance from the chemical community owing to
the highly practical nature of the transformations.[10]
Despite impressive recent advances, detailed mechanistic
understanding of these reactions remains elusive. Knowledge
of kinetics would allow the design of more-active catalysts,
and hence make a fundamental contribution to this vibrant
Figure 1. Proposed catalytic cycle for the iminium ion catalyzed Diels–
Alder reaction. Labels A–C follow the species containing the catalytic
amine group; labels D–G follow the species incorporating the starting
a,b-unsaturated carbonyl compound.
field of research. Having developed theoretical models for the
formation of iminium ions and Diels–Alder cycloaddition,[11]
we present kinetic and structural investigations into the
individual steps of a model reaction, shedding light on the
relationship between structure and activity and hence a
rationale for further catalyst development.
tion II is the key bond-formation process, while transforma-
tion III is the hydrolysis of an iminium ion to release the
reaction product and regenerate the catalyst.
We sought a suitable model system from which to obtain
kinetic data for each step I–III. After examining a range of
secondary amines, co-acids, and solvents, as well as dienes and
dienophiles, we adopted the experimental conditions outlined
in Scheme 1. 2-(Trifluoromethyl)pyrrolidine (5) is an active
Central to these reactions is the activation of an a,b-
unsaturated carbonyl compound by a secondary amine to
form an iminium ion, which is activated to cycloaddition or
nucleophilic attack. The proposed catalytic cycle for the
Diels–Alder reaction (Figure 1) comprises three main steps,
denoted I, II, and III, which involve three discrete species
containing the catalytic amine group (A–C) and four species
incorporating the starting a,b-unsaturated carbonyl com-
pound (D–G). Transformation I involves formation of the
reactive iminium ion by condensation of a secondary amine
with the a,b-unsaturated carbonyl compound. Transforma-
Scheme 1. Model reaction used in this study.
[*] Dr. G. Evans, T. J. K. Gibbs, Dr. R. L. Jenkins, Dr. J. A. Platts,
Dr. N. C. O. Tomkinson
catalyst for this prototypical Diels–Alder transformation,
with which the reaction proceeds to 93% conversion after 6 h
(10 mol% 5·HCl, 258C, 0.95m). The reaction is easily
followed by 1H and 19F NMR spectroscopy, permitting
structural elucidation of all intermediates. Importantly,
HPF6 provides stable, crystalline iminium ion intermediates
that can be stored at room temperature, easily manipulated,
and analyzed by single-crystal X-ray diffraction. This combi-
nation also provides a favorable equilibrium position for
step I (98% iminium ion), which exists as a single isomer, as
confirmed by NOESY experiments, X-ray diffraction, and
theoretical data.
School of Chemistry
Main Building, Cardiff University
Park Place, Cardiff, CF10 3AT (UK)
Fax: (+44)29-2087-4030
E-mail: platts@cardiff.ac.uk
tomkinsonnc@cardiff.ac.uk
Homepage: http://www.cardiff.ac.uk/chemy
Dr. S. J. Coles, Prof. M. B. Hursthouse
Department of Crystallography
School of Chemistry, Southampton University
Southampton, SO17 1BJ (UK)
[**] We thank the EPSRC for financial support under grant reference GR/
S69337/01, and the Mass Spectrometry Service, Swansea for high-
resolution spectra.
Cinnamaldehyde (1 equiv) was added to a solution of
5·HPF6 in CD3CN (0.25m, 293 K), and the reaction resulted in
disappearance of starting material and formation of the
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
1
iminium ion in the H NMR spectrum. No significant differ-
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ence in reactivity between 5·HCl and 5·HPF6 was observed. In
optimized geometries show much similarity (Figure 3). The
this way, the second-order rate constant for step I was
DFT data also confirm that the E isomer of the iminium ion is
determined to be
k
293 = (2.65 Æ 0.35) ” 10À3 dm3 molÀ1 sÀ1
10.6 kJmolÀ1 more stable than the Z isomer.
(Supporting Information). Carrying out the same procedure
at temperatures of 298 and 303 K established the activation
parameters Ea = (100.0 Æ 7.9) kJmolÀ1 and A = 5.89 ” 1014 sÀ1
In addition to structural characterization, isolation of this
reactive species is made possible by the stability of the PF6
salt, and hence, independent study of step II is possible.
Cyclopentadiene (3 equiv) was added to a solution of 6 in
CD3CN (0.25m, 293 K), the reaction was followed by
1H NMR spectroscopy, and the second-order rate constant
was determined to be k293 = (3.74 Æ 0.02) ” 10À4 dm3 molÀ1 sÀ1,
which is considerably slower than formation of the iminium
ion at 293 K. Rate constants at 298 and 303 K give Ea =
(45.1 Æ 1.7) kJmolÀ1 and A = 4.14 ” 104 sÀ1 (Figure 4; DH° =
(42.7 Æ 1.7) kJmolÀ1, DS° = (À164.9 Æ 5.9) JKÀ1 molÀ1). DFT
calculations support this data, giving Ea = 62.3 kJmolÀ1, which
is in reasonable agreement with experiment.
(Figure 2;
DH° = (97.5 Æ 7.8) kJmolÀ1,
DS° = (27.3 Æ
26.3) JKÀ1 molÀ1, see the Supporting Information). By DFT
calculations[11] the barrier to formation of iminium ion was
estimated to be Ea = 96.9 kJmolÀ1. Given the approximations
involved (in basis set, functional, and solvation), this agree-
ment is fortuitous but nonetheless provides reassurance that
values from experiment and theory are reliable.
Figure 2. Arrhenius plot for iminium ion formation, with standard
error of mean shown as error bars.
Figure 4. Arrhenius plot for the Diels–Alder cycloaddition, with stan-
dard error of mean shown as error bars.
Use of HPF6 allows isolation of iminium ion intermedi-
ates, and the single-crystal X-ray structure of 6 is shown in
Figure 3. This result is not unique to 5; PF6 salts of many
iminium ions can be isolated (the structure of pyrrolidi-
ne·HPF6 is reported in the Supporting Information). The
structure of 6 confirms the expected geometry, with E or-
ientation of the iminium ion and essentially coplanar arrange-
ment of the iminium ion and phenyl ring. X-ray and DFT-
Step III, hydrolysis of the product iminium ion, is
irrelevant to the overall kinetics of the catalytic cycle, as
based upon the following observations. Isolation of a Diels–
Alder cycloadduct iminium ion proved impossible, as these
compounds immediately hydrolyzed to the corresponding
aldehydes. Diels–Alder cycloaddition in the presence of a
trace amount of water initially showed formation of the
aldehyde products 3 (d = 9.85 ppm) and 4 (d = 9.54 ppm), but
after complete consumption of water, the corresponding
iminium ions 7 and 8 were observed by 1H NMR spectroscopy
(d = 8.63–8.78 ppm). The equilibrium between the Diels–
Alder adducts 3 and 4 with the catalyst 5·HPF6 shows no
indication of the corresponding iminium ions under the
reaction conditions. Finally, DFT calculations give a barrier of
73 kJmolÀ1, that is, considerably less than for step I.
These data allow us to draw several chemically relevant
conclusions. Firstly, the Diels–Alder cycloaddition (step II) is
the rate-determining step of the catalytic cycle; under the
conditions used, this step is six times slower than iminium ion
formation, despite the activation energy for step II being
Figure 3. Overlay of X-ray and DFT structures of iminium ion 6;
hydrogen atoms are omitted for clarity. Full crystal and geometrical
details are reported in the Supporting Information.
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Communications
much smaller than for step I. The Arrhenius parameter A and the future design of more-active catalysts will target this
gives rise to this kinetic profile, with A approximately 10 aspect.
orders of magnitude smaller for the cycloaddition step, as a
result of stricter steric requirements for step II. The Arrhe-
nius parameter A derived for step II is of similar magnitude to Experimental Section
Crystal data for 6: C14H15F9NP, Mr = 399.24, crystallized from
previously reported values for noncatalyzed Diels–Alder
reactions.[12]
methanol, colorless block needles, monoclinic, space group P21/c,
a = 18.5797(5), b = 10.6257(3), c = 8.38670(10) Š, b = 98.718(2)8, V=
To examine the effect of the CF3 group in 5, we compared
the reactivity of 5·HCl with pyrrolidine·HCl (9·HCl) and
proline methyl ester hydrochloride (10·HCl) as catalysts for
the Diels–Alder cycloaddition of cinnamaldehyde and cyclo-
pentadiene. Under identical reaction conditions (MeOH,
298 K, 0.95m, 10 mol% cat., 6 h), the yields of isolated
product for the transformations for 9·HCl, 10·HCl, and 5·HCl
were 5, 62, and 93%, respectively.
1636.59(7) Š3, Z = 4, 1calcd = 1.620 MgmÀ3
, T= 120(2) K; 19829
reflections collected, 3737 independent (Rint = 0.0411) which were
used in calculations R1 = 0.0395, wR2 = 0.0978 for observed unique
reflections [F2 > 2s(F2)] and R1 = 0.0530, wR2 = 0.1047 for all 3737
unique reflections. The maximum and minimum residual electron
densities on the final difference Fourier map were 0.328 and
À0.442 eŠÀ3, respectively. CCDC-657257 contains the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
The agreement between experiment and theory for steps I
and II is pleasing to note, and lends experimental support to
our theoretical studies.[11] However, experimental data show
that steric and collision parameters, accounted for in the
parameter A, are as important as activation energy. These
parameters are not accessible from single-molecule DFT
studies, such that we do not have a fully predictive theoretical
model. In the absence of these data, we sought indicators of
potential reactivity. Since cycloaddition is the rate-determin-
ing step, the LUMO energy of the dienophile should play a
major role.[13] Indeed, the ELUMO value of the iminium ion
derived from 5 and cinnamaldehyde is found to be consid-
erably lower (À2.78 eV) than that from either 9 or 10 (À2.50
and À2.61 eV, respectively). Aplot of this LUMO (Figure 5)
Received: December 4, 2007
Published online: February 29, 2008
Keywords: cycloaddition · density functional calculations ·
.
iminium ions · kinetics · organocatalysis
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