Directly probing the racemization of imidazolines by vibrational circular dichroism: Kinetics and mechanism

Article abstract of DOI:10.1021/ol100734t

(Figure presented) The first report of monitoring the kinetics of racemization in solution by online vibrational circular dichroism (VCD), chemometrics, and density functional theory (DFT) calculations is presented. The activation energy for the racemizat

Full text of DOI:10.1021/ol100734t

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2782-2785
Directly Probing the Racemization of
Imidazolines by Vibrational Circular
Dichroism: Kinetics and Mechanism
Shengli Ma, Carl A. Busacca, Keith R. Fandrick, Teresa Bartholomeyzik,
Nizar Haddad, Sherry Shen, Heewon Lee, Anjan Saha, Nathan Yee,
Chris Senanayake, and Nelu Grinberg*
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals, Inc.,
Ridgefield, Connecticut 06877
nelu.grinberg@boehringer-ingelheim.com
Received April 19, 2010
ABSTRACT
The first report of monitoring the kinetics of racemization in solution by online vibrational circular dichroism (VCD), chemometrics, and
density functional theory (DFT) calculations is presented. The activation energy for the racemization of an imidazoline based on the experimental
VCD was determined, and the detailed mechanism of the process utilizing DFT calculations was elucidated. This study demonstrates the
utility of VCD for the determination of reaction mechanisms in asymmetric transformations.
Determination of the kinetics of asymmetric transformations
is a very important task in establishing the mechanisms of
such processes. Online monitoring of asymmetric reactions
is challenging due to the limited number of techniques
available for the direct observation of such reactions.
Vibrational circular dichroism (VCD) is a demonstrated
molecular level method that can provide stereochemical
information on the behavior of specific functional groups
linked to a chiral center. VCD is generally utilized for the
determination of the absolute configuration of small chiral
molecules1,2 as well as the study of conformational changes
of biomolecules.3-6 Compared to other chiroptical methods
such as electronic CD, VCD is based on vibrational transi-
tions and thus is applicable to all types of chiral molecules,
while UV-based CD is applicable only to chromophore-
containing molecules.7-11 To date, there are only a few
reports on the application of VCD to kinetic studies of
reactions involving chiral molecules. These studies pertain
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10.1021/ol100734t  2010 American Chemical Society
Published on Web 05/20/2010

to reactions in the gas phase.12-15 To the best of our
knowledge, there are no reports on direct probing of online
kinetic studies in solution. We report here the first online
kinetic study of a racemization reaction of an imidazoline
using online VCD measurements in solution.
Scheme 1. Racemization Process
Imidazolines are valuable chiral building blocks that
have been used to construct libraries of chiral ligands
including imidazoline-amines,16 imidazoline-aminoph-
enols,17,18 imidazoline-pyrrolidines,19 and imidazoline-phos-
phines.20-24 Chiral imidazolines bearing the core of
compound 1 are effective in a number of organic transforma-
tions,25 including enantioselective hydrogenations,20,26 asym-
metric Henry reactions,27 asymmetric Heck reactions,28,29
and asymmetric Friedel-Crafts substitutions.30 Imidazoline-
containing drugs have been also used for the treatment of
cancer, central nervous system (CNS) diseases, and hyper-
tension.31-33
1 using online VCD measurements with the support of
chemometrics and density functional theory (DFT) computa-
tions. This approach has provided a direct, stereochemical
probe of the reaction and enabled the determination of both
the reaction kinetics and the reaction mechanism.
It was found that under strongly basic conditions (Scheme
1) imidazoline 1 in solution undergoes an unexpected
racemization.34 To understand this phenomenon, we present
herein the first study of the racemization of chiral imidazoline
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Figure 1. (a) VCD spectra of (S,S)-imidazoline 1 at different
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reaction times during racemization in DMSO solution at 60 °C.
(b) Relationship of ln (ee %) versus time at different temperatures.
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K. B.; O’Brien, E. M.; Qiu, F.; Simpson, R. D.; Smith, L.; So, R. C.; Spinelli,
Figure 1a presents the VCD spectra measured at different
time intervals during the racemization of (S,S)-imidazoline
1 at 60 °C. The reaction mixtures were continuously pumped
through a spectrophotometric flow cell, and the spectra were
automatically recorded with a FT-VCD instrument during
the entire course of the reaction. Due to the absorbance
interference from the solvent and reagents, we focused on
the region from 1650 to 1480 cm-1, where four distinct VCD
bands at 1615, 1600, 1570, and 1508 cm-1 can be observed.
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Org. Lett., Vol. 12, No. 12, 2010
2783

The band assignment is presented in Figure 1a as well as in
the Supporting Information. The decrease in intensity as a
function of reaction time of all four bands clearly indicates
that the imidazoline 1 undergoes racemization at 60 °C in a
DMSO-d6 solution. The VCD measurements performed at
different temperatures showed significant spectral changes
during the reaction. To determine the enantiomeric excess
we utilized chemometric calculations on the spectra region
between 1650 and 1480 cm-1. The prediction of the
enantiomeric excess (ee %) at different time intervals during
the racemization reaction at different temperatures is shown
in the Supporting Information..
A plot of the ln(ee %) versus time produced straight lines
at all temperatures examined (Figure 1b), and the activation
energy obtained from the corresponding Arrhenius plot is
∼24 kcal/mol, which corresponds approximately to a near
doubling of the rate constant with a 10 °C temperature
increase, consistent with a first-order kinetics.35,36
energy of 24 kcal/mol. The calculation also revealed that
prior to the transition state a charge dissymmetry occurs
throughout the imidazoline ring and the aromatic moieties
connected to the two chiral centers (see the Supporting
Information). Thus, the reaction may be initiated by the
mutual charge-transfer interaction between the π and the σ
bond to be broken. This interaction will take place between
the HOMO (bonding) and the LUMO (antibonding) of each
bonding region. The charge transfer from the bonding
HOMO to the antibonding LUMO37 will cause the weaken-
ing and accordingly the stretching of both bonds (Figure 2b).
An increase in bond length will cause a lowering of the
LUMO level and an elevation of the HOMO energy, so that
the charge transfer is further facilitated. Such interactions
may be assisted by vibrational motions.37,38 A conformation
search (B3LYP 6-31*) of the ring-opened product produces
three sets of enantiomers. The lowest energy of these is
intermediate 2, the direct product of the 6π ring disrotatory
ring-opening of the substrate which is 8.0 kcal/mol higher
in energy than the starting material 1. Due to the nonbonding
interactions of the cis-imine phenyl ring with the neighboring
trans-imine, the cis-imine fragment is twisted 35.4° (dihedral
angle) out of plane and thus imparts chirality to the structure
(Figure 3a). However, due to the chiral nature of the
DFT calculations on the reaction were performed to obtain
further insight into the reaction. From a series of conforma-
tional searches and reaction pathway calculations a reaction
coordinate diagram for the racemization process was con-
structed (Figure 2). The calculated transition state energy
Figure 3. (a) Calculated lowest energy conformation of intermediate
2. (b) Calculated lowest energy conformation of intermediate 3.
Figure 2
.
(a) Energy diagram of the racemization process of 1. (b)
intermediate (2), a conformational change has to take place
in order to produce the opposite enantiomer of 1 (1′). The
ring system will otherwise close to produce the same
enantiomer as the original starting material (1).
Reaction path simulation of the racemization: structure and changes
of the C-C bond length of ground, transition, and intermediate states.
for the 6π ring opening is 20.7 kcal/mol, which is in close
agreement with the experimental VCD determined activation
(35) Danel, C.; Fulon, C.; Goossens, J.-F.; Bonte, J.-P.; Vaccher, C.
Tetrahedron: Asymmetry 2006, 17, 2317–2321.
2784
Org. Lett., Vol. 12, No. 12, 2010

The next lowest energy conformer of the intermediates is
3 (Figure 3b) which is 10.5 kcal/mol higher in energy than
the starting compound 1 (as shown in Figure 2a). Intermedi-
ate 3 is a rotamer of 2, in which the cis-imine is twisted
157.4° out of plane with the trans-imine fragment. The
difference between 2 and 3 is that the cis-imine in 3 is twisted
an additional 122° out of plane relative to the opposite trans-
imine fragment. This twisting to form 3 from 2 would render
the cis-imine orthogonal to the conjugated anion (central
carbon) and thus lose the stabilization that arises from
conjugation of the anion. As the corresponding π systems
of the phenyl rings of compounds 2 and 3 are not orthogonal
to the central anion, there will still be some delocalization
(conjugation) of the central anion, and these structures would
represent the best compromise between the benefits of
conjugation and the reduction of nonbonding interactions of
the neighboring phenyl substituents.
As it would be more sterically demanding to interconvert
2 to 2* directly (via twisting the cis-imine through the trans-
imine, Figure 3a), the best process for the racemization would
be for the intermediate 2 to twist to intermediate 3 where
intermediate 3 could more easily access its enantiomer 3*
(Figure 3b). This process then would constitute the racem-
ization mechanism of the substrate through the rotation of
the cis-imine. It should be noted that a similar process can
occur with the trans-imine, but the trans-imine rotamer
similar to 3 is 1.5 kcal/mol higher in energy than 3 described
here. These results are in concert with a disrotatory pericyclic
ring-opening/closing racemization mechanism.
Scheme 2. Attempted Racemization of 5 and 6
mations using chiral imidazoline ligands bearing alkyl and
alkenyl substituents can thus be safely carried out under
strongly basic conditions without fear of racemization. In
addition, the presence of unsaturation alone (6) is not
sufficient to induce racemization, supporting the idea that
the aryl substituent induces the imidazoline racemization
process.
In summary, we have described here the first online kinetic
and mechanistic study of a racemization reaction in solution
phase using VCD spectroscopy. With the aide of chemo-
metrics and DFT computations, the spectral properties,
transition state, and activation energy of the reaction were
elucidated and showed good agreement with experimental
data, allowing detailed mechanistic information to be ob-
tained. It was found that the aromatic substituents linked to
the chiral centers play a crucial role in the racemization of
these imidazolines, due to the charge asymmetry generated
by the substituents. The racemization occurs through a
disrotatory pericyclic ring-opening and closing process
facilitated by the charge transfer between LUMO and HOMO
orbitals. This observation was further confirmed by the
stereochemical stability of chiral imidazolines lacking these
arene substituents. The combined methodologies of online
VCD, chemometrics, and DFT thus provide a powerful tool
for studying critical asymmetric transformations.
A key finding is thus the important role played by the
aromatic moiety linked to the chiral center of 1 in the
racemization process. To further explore these observations
we synthesized two chiral imidazolines in which the phenyl
groups were replaced by cyclohexyl (5) and cyclohexenyl
(6) substituents, respectively (Scheme 2). Racemization
experiments were conducted under the same conditions used
for 1. No racemization was observed for either compound 5
or 6 during the 12 h reaction at 65 °C. This result has both
practical and conceptual importance. Asymmetric transfor-
Supporting Information Available: Experimental pro-
cedures, DFT calculations, and details of VCD experiments.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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