On the intermolecular interaction of N-benzylquininium chloride or quinine with some carbonyl group containing compounds

Article abstract of DOI:10.1016/j.tetlet.2016.03.109

Interactions between N-benzylquininium chloride (Quibec) and some carbonyl group containing compounds were investigated using ¹H NMR and theoretical calculations. Results highlight the importance of the hydrogen bonding between the Quibec C-9 h

Full text of DOI:10.1016/j.tetlet.2016.03.109

Accepted Manuscript
On the intermolecular interaction of N-benzylquininium chloride or quinine
with some carbonyl group containing compounds
Thais C. Avila, Marcelo M. Reginato, Cláudio Di Vitta, Lucas C. Ducati,
Leandro H. Andrade, Liliana Marzorati
PII:
S0040-4039(16)30338-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.109
TETL 47497
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 March 2016
28 March 2016
31 March 2016
Please cite this article as: Avila, T.C., Reginato, M.M., Vitta, C.D., Ducati, L.C., Andrade, L.H., Marzorati, L., On
the intermolecular interaction of N-benzylquininium chloride or quinine with some carbonyl group containing
compounds, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.03.109
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On the intermolecular interaction of N-benzylquininium
chloride or quinine with some carbonyl group containing
compounds.
Thais C. Avila, Marcelo M. Reginato, Cláudio Di Vitta, Lucas C. Ducati, Leandro H. Andrade,
Liliana Marzorati*
Instituto de Química, Universidade de São Paulo, P.O. Box 26077 005513-970, Av. Prof.
Lineu Prestes 748, São Paulo, S.P., Brazil
*Corresponding Author E-mail: lmarzora@iq.usp.br.
ABSTRACT
Interactions between N-benzylquininium chloride (Quibec) and some carbonyl group
containing compounds were investigated using 1HNMR and theoretical calculations. Results
highlight the importance of the hydrogen bonding between the Quibec C-9 hydroxyl group
and the carbonyl oxygen in addition to - stacking between the carbonyl acceptor and the
alkaloid donor.
Keywords: chiral discrimination; Quibec; quinine; 1HNMR;
Introduction
One of the most challenging topics in modern chemistry refers to the understanding of
the origin of molecular recognition between chiral organocatalysts and achiral substrates with
all related consequences for the achievement of successful asymmetric transformations.1-3 On
the other hand, the determination of enantiomeric excesses rely on the ability of a wide range
of chiral discriminating agents to generate diastereomeric associated pairs. In both cases,
1

NMR4-5 and computational methods6,7 are powerful tools to access the mutual orientation of
the molecular partners.
In our laboratory, while dealing with chiral phase-transfer catalysts, we became
interested in investigating N-benzylquininium chloride (Quibec; 1; Figure 1) as a promoter of
enantiodifferentiation in CDCl3 solution, at room or low temperature, using 1H NMR
spectroscopy. It should be mentioned that although the mechanism of asymmetric induction
by 1 or structurally related alkaloid salts in enolate based reactions seems to be well
established,8,9 their potential for chiral molecular recognition of neutral species was less
explored.10,11 In this sense, when phosphoryl- or carbamoylquinines12-14 were used as chiral
discriminating agents, the existence of a free unhindered quinuclidine nitrogen seemed to
guarantee the enantioselection of acidic-type substrates. However, 1, devoid of such basic
site for interaction, has been reported15 to provide very similar stereochemical environments
for two enantiomeric alcohols.
On the other hand, the increased acidity of C-9 hydroxyl group of 1, as a result of the
quaternization of the quinuclidine nitrogen, could allow for an efficient hydrogen bonding to
the basic carbonyl oxygen of carbonyl or of some carboxylic acid derivatives. On the basis of
this reasoning, we decided to investigate the capability of 1, as compared to quinine, to
induce 1H NMR nonequivalence of enantiotopic nuclei pertaining to the same molecule or to
discriminate between two enantiomeric solutes. To this end, compounds 2 - 6 (Figure 1) were
prepared and submitted to 1H NMR analysis as mixtures of increasing donor/acceptor molar
ratios.
2

H3C
H3C
CH3
Cl
N
HO
N
O
H3CO
O
3
2
N
1
CH3
H3C
H3C
H
N
N
C2H5
O
O
O
6
5
4
Figure 1. Compounds of this work.
Results and Discussion
In the case of mixtures of 1 with amide 2, progressive resolution of the signal for the
methyl group into two superimposed doublets was observed by increasing the donor/acceptor
molar ratio. Better results were obtained at -20 oC, in line with the expectation of a tighter
interacting system (Figure 2). It should be mentioned that the molar ratio 1 : substrate could
not be extended beyond 2.5, due to the solubility constraints. Although the  values
showed a linear increase with increasing molar ratio, upfield shift () was more pronounced
for one of the two enantiomers (see Figure 2 in which symbols ∎ and  refer to the
enantiomers of 2).
3

0.050
0.045
0.040
0.035
0.030
0.025
0.020
0.015
0.010
0.005
0.000
in red [amide 2] = 5 mg / mL;
in green [amide 2] = 7 mg / mL;
in blue [amide 2] = 5 mg / mL, at - 20 o
C
0.0
0.5
1.0
1.5
2.0
2.5
1 / 2 molar ratio
Figure 2.  versus 1 / 2 molar ratio.
Aiming to identify the enantiomer that better fitted solvation, we decided to prepare
enantiomerically pure 2, starting from (R)-phenylpropionic acid, readily transformed into the
corresponding acid chloride to be submitted to reaction with sodium diphenylamide. In order
to ascertain enantiomeric purity, the 1H NMR spectrum of the newly prepared (R)-2 was
recorded in admixture with 1, at a molar ratio of 2.0 (1 / amide). As can be seen in Figure 3,
no racemization occurred during the preparation process, and the R configuration could be
unequivocally assigned to the enantiomer resonating at lower frequency.
4

Figure 3. Comparative 1H NMR spectra for the methyl signals of mixtures of (a) 1 / pure (R)-2
and (b) 1 / (+)2.
Surprisingly, for compound 3, no signal separation could be seen at room temperature,
even at the molar ratio of 2.5. At a lower temperature, the doublets were less resolved as
compared to compound 2. This result could be attributed either to the differential polarization
of the carbonyl groups in both compounds or to the presence of extra phenyl groups in
compound 2 favoring -stacking with the aromatic rings of 1.
Having in hand the above set of results, we decided to investigate the origin of the
chiral recognition phenomenum observed for the diastereomeric pairs of 1 / 2.
The geometrical optimizations of 1 and 2 were performed at the DFT-B97D3/cc-pVDZ
level of theory with Gaussian 09 package of program.16 In order to include dispersion and
hydrogen bonding effects, Grimme’s D3 corrections were also considered.17 Six different
conformations for each amide enantiomer, resulting from variation of the dihedral angle H-C-
C=O, and the optimized conformation of the chiral discriminator were assembled into 24
pairs, in which the additive (1) was placed to the left or to the right sides of the amide
molecule, favoring the larger number of intermolecular interactions. Figure 4 shows two
examples of such pairs, for which the hydrogen bond (amide C=O / C-9 OH group of 1) and
-stacking interactions are highlighted in black and red, respectively.
Figure 4. 1 / substrate pairs for: (I) (R)-2; (II) (S)-2 (optimized at B97D3/cc-pVDZ level of
theory) for 1 placed to the left of 2, considering the green dot as the chloride ion.
5

As for the (R)-enantiomer the relative energies of the 12 pairs for which 1 is placed
either to the right or to the left sides are shown in Table 1. Analogously, the relative energies
for the 12 pairs of the (S)-enantiomer are reported in Table 2.
Table 1.
Relative energies (kcal mol-1) for the arrangements of 1 placed to the left (column A) or to the
right (column B) sides of several conformations of (R)-2 optimized at B97D3/cc-pVDZ level of
theory. The relative energies in respect to global most stable conformer are shown in
parentheses.
A
B
entry Conformation
E kcal.mol-1
E kcal.mol-1
E a.u.
E a.u.
4.18
3.95
1
-2708.14945
-2708.14650
(4.18)
(6.03)
4.18
2.36
2
3
-2708.14945
-2708.15611
-2708.14903
-2708.14896
(4.18)
(4.44)
0.00
2.40
(0.00)
(4.49)
converged to the most stable conformer
for this arrangement
converged to the most stable conformer
for this arrangement
4
5
6
1.51
-2708.15369
0.00
-2708.15279
(1.51)
(2.08)
5.40
-2708.14750
4.25
-2708.146006
(5.40)
(6.34)
Table 2.
6

Relative energies (kcal mol-1) for the arrangements of 1 placed to the left (column C) or to the
right (column D) sides of several conformations of (S)-2 optimized at B97D3/cc-pVDZ level of
theory. The relative energies in respect to global most stable conformer are shown in
parentheses.
C
D
entry Conformation
E kcal.mol-1
E kcal.mol-1
E a.u.
E a.u.
converged to the fourth most stable
conformer for this arrangement
5.80
1
-2708.14657
(5.80)
2.17
-2708.15115
5.80
2
3
4
-2708.14657
-2708.15582
(2.93)
(5.80)
0.45
-2708.15388
0.00
(1.22)
(0.00)
1.13
-2708.15281
converged to the most stable conformer
for this arrangement
(1.89)
0.00
-2708.15461
converged to the most stable conformer
for this arrangement
5
6
(0.76)
converged to the most stable conformer
for this arrangement
converged to the second most stable
conformer for this arrangement
7

Considering the global most stable arrangements of the (R)-enantiomer with 1 placed to
its left side (entry 3-column A) or to its right side (entry 5-column B), the relative energy
difference is 2.08 kcal.mol-1 in favor of that in entry 3-column A (Table 1).
On the other hand, according to Table 2, for the (S)-enantiomer, the global most stable
arrangements are those in entry 3-column D and in entry 5-column C. The relative energy
difference is 0.76 kcal.mol-1 in favor of this first arrangement.
For both arrangements (entry 3-column A (Table 1) and entry 3-column D (Table 2)) the
steric repulsion between the phenyl group linked to the stereogenic center and 1 overcomes
any possible stabilization by -stacking. Although at B97D3/cc-pVDZ level of theory there is no
preference between these two arrangements (only 0.18 kcal.mol-1 in favor of (R)-2 / 1
arrangement), after their re-optimization, including PCM solvent effects (CDCl3), at B97D3/cc-
pVTZ level of theory18 (and using counterpoise corrections19), the energy difference became E
= 2.12 kcal.mol-1 and G = 2.37 kcal.mol-1 in favor of that of entry 3-column D (Table 2).
Considering the two most stable arrangements, the upfield shift of the 1H NMR doublet for
both enantiomers can be explained by the anisotropic effect of the aromatic ring of 1 on the
methyl group of 2. However, it should be noted that for the pair with the (R)-enantiomer (at the
left side in Figure 6) the methyl group is better positioned towards the shielding region of the
aromatic ring as compared to the pair with the (S)-enantiomer (at the right side in Figure 5).
Furthermore, a stronger interaction between aromatic rings for the (R)-enantiomer as compared
to the (S)-isomer (quinoline-phenyl vs phenyl-phenyl) is expected. In fact, the counterpoise
calculations for these two arrangements are -32.88 and -30.46 kcal mol-1, respectively,
amounting to a difference of 2.42 kcal mol-1. Therefore, the better quinoline-phenyl interaction
seems to be responsible for the higher stabilization for the arrangement shown in entry 3-
column A (Table 1) leading to a higher value for the 1 / (R)-2 diastereomeric pair. Theoretical
1H chemical shift calculations at IEFPCM(CDCl3)-B3LYP/cc-pVTZ level of theory corroborates
this assumption as the values for the methyl groups of 2 in arrangements shown in entry 3-
column A (Table 1) and in entry 3-column D (Table 2), are 0.7 ppm and 1.0 ppm, respectively.
8

Figure 5. The most stable pairs at IEFPCM-B97D3/cc-pVTZ level of theory, considering the
green dot as the chloride ion.
In a set of similar experiments, the 1H NMR spectra of mixtures of 1 and compounds 3 or
4 were recorded. Figures 6 and 7 (in which symbols ∎ and  refer to the enantiomers of each
compound) present the experimental vs 1 / substrate molar ratios for these compounds at
two different temperatures.
0.015
0.014
in red [3] = 5 mg / mL
in blue [3] = 5 mg / mL, at - 20 o
0.013
0.012
0.011
0.010
0.009
0.008
0.007
0.006
0.005
0.004
0.003
0.002
0.001
0.000
C
0.0
0.5
1.0
1.5
2.0
2.5
1 / 3 molar ratio
Figure 6.  versus 1 / 3 molar ratio.
9

0.010
0.009
0.008
0.007
0.006
0.005
0.004
0.003
0.002
0.001
0.000
in red [4] = 5 mg / mL
in blue [4] = 3 mg / mL, at - 20 o
C
0.0
0.5
1.0
1.5
2.0
2.5
1 / 4 molar ratio
Figure 7.  versus 1 / 4 molar ratio.
For both carbonyl compounds 3 and 4 lower  values were observed as compared to
those for compound 2 (Figures 2, 6 and 7). This seems to be in line with the expected basicity
order: amide > aldehyde > ketone. Additionally, for compounds 3 and 4, lower  values were
also observed (Table 3).
Table 3.
values for mixtures of 1 and substrates 2 - 4 (5 mg / mL), at the 2.5 : 1 (1 : substrate) molar
ratio.
Compound
(ppm
(-20 oC)
(r. t.)
2
3
4
0.0092 (0.0126)* 0.0310
0.0033
0.0024
0.0083
0.0049**
* substrate concentration: 7 mg / mL
** substrate concentration: 3 mg / mL
The comparison of spectral data for racemic 3 and of pure (R)-3-phenyl-2-butanone
(prepared from (R)-phenylpropanoic acid and 2 mol equivalents of methyllitium) allowed for the
assignment of R configuration to the ketone isomer for which the corresponding solvate
resonates at a lower frequency.
10

In order to test the importance of the -phenyl moiety as a promoter of interaction with 1,
analogous experiments were performed with 2-methylundecanal. In fact, no resolution could be
obtained for the enantiomers of the latter compound, even at a low temperature. Furthermore,
for compound 5, no separation for the 1H NMR methyl doublet could be seen at room
temperature, even at the molar ratio of 2.5. However, at lower temperature (- 20 oC), resolution
could be achieved, but  values were smaller than for compound 2 (0.0063 versus 0.0310
ppm).
Interestingly, even the -carbonyl enantiotopic protons of N,N-diphenylphenylacetamide
(6), devoid of a carbon stereocenter, could be separated into two doublets in presence of 1, at -
20 oC and at 2.5 molar ratio (Table 4).
Table 4.
 values for mixtures of 1 and 6 (5 mg / mL), at different molar ratios, at room temperature
and at -20 oC.
ppm
1 : 6
(-20 oC)
0 ( = 3.6643 ppm) 0 ( = 3.6643 ppm)
molar ratio
(r. t.)
0
0.5
1.0
1.5
2.0
2.5
0.0407
0.0497
0.0508
0,0558
0.0565
0.0518
0.0737
0.0904
0.0927
0.1157
As opposed to 1, quinine showed to be an inefficient chiral auxiliary for 1H NMR signal
resolution for substrates 2 - 6. On the contrary, enantiodiscrimination of methyl protons of each
enantiomer of 2-phenyl-1-propanol could only be achieved in the presence of quinine. In this
case, for both enantiomers, downfield shifts could be observed at room temperature or at -20 oC
(Table 5).
Table 5.
 values for mixtures of quinine and 2-phenyl-1-propanol (5 mg / mL) for different molar
ratios, at room temperature and at -20 oC.
11

(ppm)
quinine : 2-phenyl-1-propanol
molar ratio
(r. t.)
(-20 oC)
0
0 ( = 1.2552 ppm) 0 ( = 1.2680 ppm)
0.5
1.0
1.5
2.0
2.5
0
0
0.0013
0.0020
0.0024
0.0030
0.0043
0.0051
0.0066
0.0071
The R configuration of the better interacting enantiomer of 2-phenyl-1-propanol could be
assigned by comparison of 1H NMR spectral data of racemic quinine solvates with those for
solvates of quinine and an (R)-enriched mixture (e.e. 27%) of the same alcohol, prepared by
biocatalytic resolution.
Conclusion
The alkaloid salt 1 is an effective chiral discriminating agent for carbonyl and carboxyl
compounds 2 – 5. For compounds 3 and 4 lower  and values were observed as
compared to those for compound 2. This seems to be in line with the expected basicity order
amide > aldehyde > ketone. Such comparative results point to the importance of the hydrogen
bonding between the C-9 hydroxyl group of 1, and the carbonyl oxygen. Theoretical calculations
showed that the - interactions are responsible for the higher stability of the diastereomeric
pair 1 / (R)-2.
Acknowledgements
We thank FAPESP, CNPq and CAPES for financial support. We also thank Prof. Dr.
Cláudio Francisco Tormena for some previous calculations regarding compound 2.
Supplementary data
See supplementary data for experimental procedures, spectral data and other files associated
to this work.
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14

Graphical abstract
CH3
Quibec
Ph
Ph
N
Ph
O
2
Highlights
Chiral discrimination of carbonyl group containing compounds was achieved using
Quibec.
Basic amides are better discriminated than ketones and aldehydes.
Chiral discrimination relies on - stacking and hydrogen bonding interactions.
15