2,2′-dihydroxybenzil: A stereodynamic probe for primary amines controlled by steric strain

Article abstract of DOI:10.1021/ol501088v

A rational approach for generating 1,1′-binaphthalene-like axial chirality of a small organic receptor, 2,2′-dihydroxybenzil is presented. The receptor combines with 2 equiv of monodentate primary amines to form a diimine, of which axial chirality is controlled by steric strain with moderate (1.4:1) to good (4.7:1) stereoselectivity. The observed circular dichroism (CD) spectra have been closely simulated by TD-DFT computations and can be used for determining the absolute chirality and enantiomeric excess of primary amines.

Full text of DOI:10.1021/ol501088v

Letter
pubs.acs.org/OrgLett
2,2′-Dihydroxybenzil: A Stereodynamic Probe for Primary Amines
Controlled by Steric Strain
Min-Seob Seo,†,‡ Ansoo Lee,†,‡ and Hyunwoo Kim*,†,‡
†Department of Chemistry, KAIST, Daejeon 305-701, Korea
‡Center for Nanomaterials and Chemical Reactions, Institute for Basic Science (IBS), Daejeon 305-701, Korea
S
* Supporting Information
ABSTRACT: A rational approach for generating 1,1′-binaphthalene-
like axial chirality of a small organic receptor, 2,2′-dihydroxybenzil is
presented. The receptor combines with 2 equiv of monodentate
primary amines to form a diimine, of which axial chirality is
controlled by steric strain with moderate (1.4:1) to good (4.7:1)
stereoselectivity. The observed circular dichroism (CD) spectra have
been closely simulated by TD-DFT computations and can be used
for determining the absolute chirality and enantiomeric excess of primary amines.
Scheme 1. Axial Chirality of (a) 1,1′-Binaphthalene and (b)
2,2′-Dihydroxybenzil (1) and Selective Generation of Axial
Stereoisomers of a Diimine (2) Formed from 1 and 2 equiv
of (R)-3,3-Dimethyl-2-butylamine
hirality transfer from central carbons to metals, helices,
Cand molecular self-assemblies has been the topic of much
interest in catalysis, supramolecular chemistry, material science,
and pharmaceuticals.1 In particular, such chirality transfer can
be the principle of induced circular dichroism (ICD) analysis
for signal amplification of UV-silent substrates.2 The ICD
analysis has been used for fast, convenient, sensitive, and
accurate determination of the configuration and enantiomeric
excess (ee) of chiral analytes such as amines,3 alcohols,4
carboxylic acids,5 and others.6 One of the remaining challenges
is to achieve chiral sensing of monodentate chiral analytes in
the absence of any secondary interactions such as hydrogen
bonding, which could assist the axial arrangement. The
reported stereodynamic probes for sensing chiral monodentate
primary amines include arylacetylenes,7 ethane-bridged bis(zinc
porphyrin),8 m-quarterphenyls,9 and binaphtholate boron and
zinc complexes;10 however, most probes are not readily
available due to their lengthy synthetic procedures. Recently,
Anslyn and co-workers have reported in situ helical assemblies
of ZnII and FeII complexes for sensing secondary alcohols11 and
primary amines,12 respectively. These elegant systems showed a
strong chiroptical response and broad sensing scope of
monodentate chiral analytes; however, it is quite difficult to
understand the origin of stereoselectivity owing to the many
possible conformers and stereoisomers. We became interested
in the rational design of a small organic compound with
minimal structural requirements for signal amplification of
monodentate chiral analytes. Herein we report a remarkably
simple 2,2′-dihydroxybenzil (1) that generates axial chirality
with monodentate chiral primary amines.
RR-2 and M-RR-2 (Scheme 1b). We first attempted to
determine the thermodynamic ratio between the diastereomeric
axial conformers 2.
When 5 equiv of (R)-3,3-dimethyl-2-butylamine were heated
with 1 in EtOH at 80 °C for 6 h, a clean product of diimine (2)
1
was obtained. H NMR spectra of the crude mixture showed
that the diastereomeric ratio was 4.5:1 in CDCl3. Interestingly,
similar values were obtained in DMSO-d6 (4.5:1), CD3CN
(4.3:1), and CD3OD (4.7:1), indicating that the solvent effects
are not significant to the stereoselectivity of axial stereoisomers
2. Since the solvent effects are relatively small, it appears that
We propose that 2,2′-dihydroxybenzil (1) with two internal
H-bonds exhibits a 1,1′-binaphthalene-like axial arrangement
(Scheme 1). The two axial stereoisomers, P-1 and M-1, rapidly
interconvert and exist as a 1:1 mixture. When an enantiopure
primary amine, (R)-3,3-dimethyl-2-butylamine, reacts with 1 to
form a diimine 2, two stereoisomers become diastereomers, P-
Received: April 15, 2014
Published: May 12, 2014
© 2014 American Chemical Society
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Letter
the intramolecular steric interactions play a major role in
favoring the formation of one axial stereoisomer of 2.
The axial arrangement of RR-2 can be verified using circular
dichroism (CD) spectroscopy. As shown in Figure 2, there are
In order to understand the origin of stereoselectivity, we
performed DFT computations to calculate the energetics of the
two diastereomers, P-RR-2 and M-RR-2.13 The global energy
minimum structures showed that two internal hydrogen bonds
are maintained between the phenolic hydrogen and the imine
nitrogen; at the same time, the hydrogens on the chiral carbons
are facing each other, as depicted in Scheme 1b. Such hydrogen
bonding, also called the resonance-assisted hydrogen bonding
(RAHB),14 is a class of strong hydrogen bonding reinforced by
delocalization of π-bonds. According to the DFT computation
for RR-2, the M-form is more stable than the P-form by about
0.9 kcal/mol. This calculated energy difference translates to an
equilibrium ratio of 4.5:1 at 25 °C, which is in excellent
agreement with the experimental value of 4.5:1. Moreover, the
calculation indicates potential steric interactions in P-RR-2 and
M-RR-2. First, the hydrogens on the chiral carbons are facing
each other, thereby reducing the steric repulsion between the
two chiral amines in 2 (Figure 1a). With this fixed arrangement
Figure 2. (a) Measured CD spectrum and (b) UV−vis spectrum of
RR-2 (75 μM in ethanol, 10 mm cell, at 20 °C), (c) measured CD
spectrum, and (d) UV−vis spectrum of RR-2 (75 μM in acetonitrile,
10 mm cell, at 20 °C) and (e) simulated CD spectrum of M-RR-2
(TD-SCF, CAM-B3LYP/6-31G(d,p)).
strong Cotton effects in the CD spectra of RR-2. Again, the
solvent effect is negligible to provide the closely overlapped CD
spectra in ethanol and acetonitrile (Figure 2a and 2c). The 1,1′-
binaphthalene-like axial structure of 2,2′-dihydroxybenzil is
crucial for the chiroptical signals because neither salicylaldehyde
nor 2,2′-dihydroxybenzophenone yielded any active CD signals
during the formation of imines with (R)-3,3-dimethyl-2-
butylamine (Supporting Information). It is known that the
exciton coupling of chromophores can be used to assign the
absolute chirality. However, the bisignate CD curves at 340 nm
predict a P-configuration of RR-2 that is opposite to that of the
calculation and X-ray results. The failure of the exciton chirality
analysis is due to the dihedral angles of the imines. The imine
dihedral angles of the calculated and crystal structure of RR-2
are 88.5° and 90.3°, respectively. According to the theory of
exciton coupling, when dihedral angles are 0° and 90°, the CD
coupling of two degenerate electric dipole moments is zero.15
Instead, we simulated the CD spectra by performing TD-DFT
calculations (Figure 2e).13 When the bisignate CD curves
overlap at 340 nm, the simulated CD signals are well-matched
with the experimental CD signals for the first positive and the
second negative Cotton effects.
In principle, a racemic amine reacted with 1 to form eight
possible stereoisomers (Scheme 2). In our experiment, the
1.2:1 ratio of homo- and heterodiimine was obtained when an
excess amount of rac-3,3-dimethyl-2-butylamine was used. The
homodiimine is slightly more stable than the heterodiimine,
and the equilibrium is established by a statistical distribution.
Interestingly, the stereochemical analysis indicates that optical
signals of heterodiimines become zero because they are all
identical or racemic (Scheme 2). Thus, the observed optical
response could be in a linear relationship with the enantiomeric
excess of the chiral amines, as found in other studies of
chiroptical probes. Indeed, there is an excellent linear
relationship between the enantiopurities of 3,3-dimethyl-2-
butylamine and the observed CD signals (Figure 3).
Figure 1. (a) Calculated global energy minimum of M-RR-2 (DFT
B3LYP/6-31G(d,p)) and (b) crystal structure (50% ellipsoid
probability) of RR-2. All hydrogens except for phenols and chirality
carbon centers are omitted for clarity.
of chiral amines, additional steric repulsion appears between the
substituents (Me or tert-Bu groups) on the chiral carbons and
the phenol rings (Figure 1a). In the case of RR-2, the Me
groups are placed near the phenol rings in the M form while the
tert-Bu groups are placed near the phenol rings in the P form.
Thus, M-RR-2 is more stable than P-RR-2, allowing it to reduce
the steric repulsion. Indeed, the crystal structure of RR-2
showed an M-configuration, with two internal H-bonds as well
as a fixed orientation of amines (Figure 1b). Therefore, there is
excellent agreement between the DFT computations and the
1
experimental results, such as H NMR and X-ray analysis.
Consistent with the X-ray data (Figure 1b), RR-2 was
1
selectively crystallized to M-RR-2. The H NMR spectra of M-
RR-2 showed that equilibrium was established within hours at
ambient temperature. Then, we carried out kinetic studies by
monitoring the reaction by 1H NMR spectroscopy (CDCl3, 10
mM) at various temperatures (40 to 55 °C, Supporting
Information). The resulting linear Eyring plot gave us values of
ΔH‡ and ΔS‡ for the forward reaction from P-RR-2 to M-RR-2
of 14.2 kcal/mol and −29.2 cal/mol, respectively. Similarly, the
values of the activation parameters, ΔH‡ and ΔS‡, of the
backward reaction from M-RR-2 to P-RR-2 were found to be
15.0 kcal/mol and −29.3 cal/mol, respectively. Thus, we were
able to determine the rotation barriers (ΔG‡ = 22.9 and 23.8
kcal/mol) and the free energy change (ΔG = 0.9 kcal/mol) at
25 °C.
Since we have shown that the axial arrangement of 1 can be
controlled by the steric effect of chiral amines, we have
determined the stereoselectivities of a variety of chiral amines
(Table 1). When monodentate chiral amines were used,
moderate (1.4:1) to good (4.7:1) stereoselectivities were
obtained. It appears that the steric difference between two
substrates of chiral amines correlates with the stereoselectivity
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Scheme 2. Eight Possible Stereoisomers and Their
Relationship in the Formation of Diimine between 1 and
rac-3,3-Dimethyl-2-butylamine
Table 1. Stereoselective Chirality Transfer from
Monodentate Primary Amines to 2,2′-Dihydroxybenzil (1)
a
b
1
Determined by H NMR spectra. 75 μM in ethanol, 10 mm cell, at
20 °C.
experimental CD spectra can be used to determine the absolute
chirality of primary amines.
In conclusion, using an exceptionally simple 1,1′-binaph-
thalene-like axial compound, 2,2′-dihydroxybenzil (1), we have
demonstrated a rational approach for signal amplification of
primary amines. The axial chirality of the stereodynamic
receptor is controlled by forming diimines with a series of
monodentate primary amines that have moderate (1.4:1) to
good (4.7:1) stereoselectivity. The origin of stereoselectivity
can be unambiguously explained by combining the exper-
imental data, such as that from the 1H NMR and CD
spectroscopy and the X-ray crystallography, with computational
data from geometry optimization and electronic CD simulation.
Furthermore, the stereodynamic receptor can be used for the
accurate determination of the value of ee and the absolute
configuration of the primary amines.
Figure 3. (a) Circular dichroism spectra of 2 with varied
enantiopurities of 3,3-dimethyl-2-butylamine and (b) a linear plot
between CD/UV−vis ratios and enantiopurities of 3,3-dimethyl-2-
butylamine (75 μM in ethanol, 10 mm cell, at 20 °C).
of axial conformers. Remarkably, a subtle difference between
methyl and ethyl groups in 2-aminobutane also gave a
meaningful diastereoselectivity of 1.4:1, as well as strong CD
signals (Table 1, entry 1). Although exciton chirality is not
applicable for determining absolute chirality, our CD spectra
indicate that the signal of the first Cotton effect at 320−340 nm
can be used to assign the absolute chirality of primary amines.
(R)-Amines with alkyl substituents gave positive first Cotton
effects (entries 1−3), while (R)-amines with aryl-alkyl
substituents gave negative first Cotton effects (entries 4−7).
The CD spectra for a diimine between 1 and (R)-2-methyl
benzylamine (entry 4) was also closely simulated by TD-DFT
computation (Supporting Information). We reasoned that the
electric dipole moments of imines strongly coupled with those
of aryl substituents, overriding the possible imine−imine
couple. On the basis of the CD and computational data, we
can rationalize that all (R)-amines selectively form M-axial
conformers that give negative or positive first Cotton effects
with regard to the alkyl or aryl substituents of the amines. Thus,
ASSOCIATED CONTENT
* Supporting Information
Synthetic procedures, and spectroscopic, spectrometric, calcu-
lation, and crystallographic details. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hwkim@kaist.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Research Foundation of Korea
(NRF 2011-0014197) and the Institute for Basic Sciences
(IBS) for supporting this research. M.-S.S. acknowledges
financial support from the Kwanjeong Education Foundation.
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