Application of chemical shifts in 1H and 13C NMR spectra to configuration assignment of Schiff bases in the liquid phase

Article abstract of DOI:10.1134/S1070428013080046

In ¹H and ¹³C NMR spectra of N-substituted dimethylketimines chemical shifts of protons and carbon atoms of the methyl groups in the cis-position with respect to the unshared electron pair of the nitrogen are larger than those of the CH₃ groups in the trans-position by 0.2-0.4 and 8-11 ppm respectively. This effect is accompanied by the reduction of the corresponding direct spin-spin coupling constant ¹³C-¹³C by 10 Hz. The experimental trends in the variation of the spectral parameters are well reproduced by ab initio quantum-chemical calculations. The discovered stereochemical dependence of the chemical shifts of ¹H and ¹³C may underlie a simple and efficient method of the configuration assignment in various compounds with a C=N bond.

Full text of DOI:10.1134/S1070428013080046

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 8, pp. 1117−1121. © Pleiades Publishing, Ltd., 2013.
Original English Text © A.V. Afonin, D.V. Pavlov, I.A. Ushakov, E.P. Levanova, G.G. Levkovskaya, 2013, published in Zhurnal Organicheskoi Khimii, 2013,
Vol. 49, No. 8, pp. 1136−1140.
1
13
Application of Chemical Shifts in Н and С NMR Spectra
to Configuration Assignment of Schiff Bases
in the Liquid Phase
A. V. Afonin, D. V. Pavlov, I. A. Ushakov, E. P. Levanova, and G. G. Levkovskaya
Faworsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
Irkutsk, 664033 Russia
e-mail: andvalaf@mail.ru
Received February 9, 2013
1
13
Abstract—In Н and С NMR spectra of N-substituted dimethylketimines chemical shifts of protons and carbon
atoms of the methyl groups in the cis-position with respect to the unshared electron pair of the nitrogen are larger
than those of the СН groups in the trans-position by 0.2–0.4 and 8–11 ppm respectively. This effect is accompanied
3
13
13
by the reduction of the corresponding direct spin-spin coupling constant С– С by 10 Hz. The experimental trends
in the variation of the spectral parameters are well reproduced by ab initio quantum-chemical calculations. The
1
13
discovered stereochemical dependence of the chemical shifts of Н and С may underlie a simple and efficient
method of the configuration assignment in various compounds with a С=N bond.
DOI: 10.1134/S1070428013080046
Azomethine compounds (Schiff bases) already for a from the data of IR and Raman spectroscopy [5–9]. The
1
3
long time have been utilized in analytic, synthetic, theo-
С NMR spectra of solid substances were extensively
retical chemistry, and their potential is far from being used to this end [10–13], and in the liquid phase the ex-
1
exhausted. They have found a wide application in the periments of nucleаr Overhauser effect in the Н NMR
synthetic organic chemistry, in particular, in the synthesis spectra (homonuclear NOESY) were often utilized [14].
of heterocyclic compounds, secondary amines, for the However the mentioned methods have a number of es-
protection of the carbonyl function [1].
sential disadvantages. The analysis of IR and Raman
spectra is complicated by mixing of vibration modes
Nowadays the investigation of their structure, proper-
ties, and the synthesis is performed with the use of modern leading to the difficulties in the assignment of the bands
strategy. In [2] a method was developed of the preparation of absorption or scattering. The interpretation of the data
of a series of aryl-, heterylimines by a catalytic oxida- of homonuclear NOESY can be ambiguous for complex
tion of secondary and tertiary amines under the action of spin systems, especially at the overlapping of multiplets
visible light. In keeping with the principles of the green and signal broadening in the event of the intramolecular
chemistry and using the microwave irradiation the syn- chemical exchange or conformational lability. The data
thesis of new Schiff bases was performed which not only obtained in the solid phase may be unlike the state of the
exhibited the antioxidant and antitumor action but were molecule in solution where most of the reactions occur.
very promising for further transformations [3]. A series
of well known practically used imines were obtained on
the aluminum oxide in mild conditions without solvent
in the yield up to 99% [4].
We formerly examined the stereospecificity of the
chemical shifts in the С NMR spectra of oximes, azines,
13
and hydrazones in solutions. We demonstrated the ef-
13
ficiency of the application of the С chemical shifts to
The configuration of Schiff bases with respect to evaluation of the configuration of compounds containing a
the C=N bond was commonly determined proceeding C=N– bond [15–20]. By the comparison of experimental
1117

1118
AFONIN et al.
13С chemical shifts and those calculated in the framework
of the theory of density functional we establisted the con-
figuration of some heteroaromatic Schiff bases in solution
(V) are compiled in Tables 1, 2, the values of the direct
С– С coupling constants for compounds I, IV, V, in
Table 3.
1
3
13
[
3]. However the configurational assignment in this case
As seen from the data of Table 2, the chemical shifts
of С atoms of the methyl groups of ketimines I–III are
considerably different. This difference originates from
the different spatial orientation of the methyl groups with
respect to the substituent at the nitrogen atom and to the
unshared electron pair of the latter.
was performed at the presence of a single isomer thus
preventing the extension of the data obtained on a wider
range of Schiff bases.Aiming to obtain more reliable data
on the stereospecificity of the chemical shifts in the NMR
spectra of Schiff bases in solution we studied in this work
13
1
13
Н and С NMR spectra of some simplest specimen of
this class compounds, N-substituted dimethylketimines,
1
3
To assign the signals of С of the methyl groups we
1
3
13
measured direct coupling constants С– С. The direct
13
13
and measured the direct С– С coupling constants. The
data obtained were compared with analogous data for ac-
etone oxime and acetone azine where the stereospecificity
of NMR spectral parameters had been established before
13
13
spin-spin coupling constants С– С are known to exhibit
a pronounced stereochemical dependence with respect to
the spatial orientation of the unshared electron pair of the
contiguous nitrogen atom, and the coupling constant for
the С–С bond located n the cis-position with respect to
the unshared electron pair is significantly larger than that
for the bond in the trans-position [21, 22]. For instance,
in acetone azine (IV) the value of the direct coupling
[19]. The reliability of the obtained experimental data
was confirmed by theoretical calculations. The measured
chemical shift values in the H and С NMR spectra of
ketimines I–III, acetone azine (IV), and acetone oxime
1
13
1
Table 1. Chemical shifts in H NMR spectra of ketimines I–III, acetone azine (IV), and acetone oxime (V), δ, ppm
2
3
о
м
п
2
3
Compound no.
H -trans
H -cis
CH2
H (H )
H (H )
H (H )
Δδ = δ(H ) – δ(H )
A
B
X
1.75 (1.66)а
I
2.19 (2.11)
6.68
7.33
5.06
7.25
7.33
5.14
7.02
7.33
5.98
–0.44 ( 0.45)
II
III
IV
V
1.92 (1.65)
1.82 (1.72)
1.74
2.10 (1.98)
2.02 (1.94)
1.85
4.46
3.89
–0.18 ( 0.33)
–0.20 ( 0.22)
–0.11
1.87
1.88
–0.01
а
In parentheses are given the data of chemical shifts calculation by the method GIAO on the level МР2/6-311G(3df,p).
Table 2. Chemical shifts in 13C NMR spectra of ketimines I–III, acetone azine (IV), and acetone oxime (V), δ, ppm
Compound no. C1
C -trans
2
C -cis
3
CH2
C (C ) C (C )
и
α
о
β
Cм
Cп
Δδ = δ(С ) – δ(С )
2
3
I
169.04 20.49 (22.93)а 28.49 (32.06)
151.30 119.54 128.80 123.01 –8.0 ( 9.1)
140.32 127.76 128.34 126.46 –10.7 (–13.5)
II
168.09 18.70 (20.55)
167.80 18.03 (19.45)
159.18 17.12
29.38 (34.09) 55.37
28.98 (34.18) 53.89
24.54
21.81
III
IVb
Vb
135.91 114.74
–11.0 (–14.7)
–7.4
155.26 14.95
–6.9
а
In parentheses are given the data of chemical shifts calculation by the method GIAO on the level МР2/6-311G(3df,p).
Data of [19] are given.
b
Table 3. Direct coupling constants 13C− C (Hz) for ketimine I, acetone azine (IV), and acetone oxime (V)
13
1
1
2
1
1
3
1
1
2
1
1
3
Compound no.
J(C ,C )-trans
J(C ,C )-cis
ΔJ = J(C ,C ) – J(C ,C )
I
38.2 (39.5)а
40.0
48.6 (49.4)
50.2
–10.4 (–9.9)
–10.2
IVb
Vb
41.2
49.8
–8.6
а
In parentheses are given the data of coupling constants calculation by the method CP-KS on the level B3LYP/6-311G(3df,p).
Data of [19] are given.
b
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 8 2013

APPLICATION OF CHEMICAL SHIFTS
1119
13
13
constant С– С of the methyl group in the cis-position
exceeds by 10.2 Hz analogous value of the methyl group
in the trans-position (Table 3); this difference for acetone
oxime (V) is 8.6 Hz.
compounds I–III is considerably larger than that of the
methyl groups in the trans-position. For ketimines II,
III the difference in the mentioned chemical shifts ∆δ
is ~0.2 ppm, whereas in ketimine I ∆δ increases up to
0
.44 ppm (Table 1). The protons of the trans-СН group
In ketimine I one of the direct coupling constants
3
1
3
13
are affected by the anisotropy of the aromatic ring and
suffer an additional shielding [23], and this explains the
increased difference in the chemical shifts of the protons
of trans- and cis-methyl groups.
С– С involving the carbon atoms of the methyl groups
is also larger than another by 10.4 Hz (Table 3). This
1
3
13
means that the larger direct coupling constant С– С
48.6 Hz) and the corresponding to this coupling signal
(
13
of the atom С at 28.5 ppm belong to the СН group with
The observed stereochemical regularities in the param-
3
1
13
the cis-orientation with respect to the unshared electron
eters of Н and С NMR spectra of ketimines I–III are
successfully reproduced by quantum-chemical calcula-
tions. The calculation was performed using the program
GAUSSIAN 09 [24]. The geometry of ketimines I–III
was optimized with accounting for the electron correla-
tion at the level МР2 using basis set 6-311G(d,p). In the
equilibrium geometric forms of molecule I corresponding
to the energy minimum the benzene ring notably devi-
ates from the plane of the azomethine group, the dihedral
angle Ψ between the planes of groups >C=N– and Ph is
pair of the nitrogen atom. For the СН group with the
3
1
trans-position the respective values are J(C,C) 38.2 Hz,
13
chemical shift C 20.5 ppm. These data suggest to assign
1
3
the high-frequency peak of the methyl group in the C
NMR spectrum of ketimines II, III to cis-СН group, and
3
the low-frequency peak, to trans-СН groups (~29 and
3
1
8–19 ppm respectively).
1
3
Thus the shielding constants of the С nuclei of СН
3
groups and the chemical shifts in Schiff bases I–III are
1
13
1
3
73°. The chemical shift values of Н and С calculated
by the method of calibrating independent atomic orbitals
stereospecific. The carbon С nucleus of trans-СН3
groups is more shielded by 8–11 ppm compared with that
(GIAO) [25] are listed in Tables 1 and 2, and the coupling
of the cis-СН groups. In acetone azine (IV) and acetone
3
1
3
13
constants С– С calculated by the method of bound-
state perturbations (CP-KS) [26] are given in Table 3.
oxime (V) the same regularity is observed: The chemi-
cal shift of the carbon atom of the trans-СН group is by
3
~
7 ppm smaller than that of the cis-СН group (Table 2).
The averaged values of the calculated chemical shifts
of the methyl groups protons are presented in Table 1;
3
In going from trans-СН to cis-СН in ketimines
3
3
for the protons of the trans-СН group the chemical
I–III the systematic variation in the chemical shifts is
observed not only for С nuclei, but also for protons. The
assignment of Н signals of trans- and cis-СН groups
in the molecules I–III was performed proceeding from
3
13
shifts are lower than for cis-СН groups. The maximum
3
1
difference of the theoretical values Δδ was found for
ketimine I. Therewith the observed agreement between
the calculated and measured values of Δδ (–0.45 and
–0.44 ppm respectively) is very close. According to the
calculation, in ketimines II and IIIΔδ decreases to –0.33
and –0.22 ppm respectively, in conformity with the ex-
3
the presence of the cross-peaks with the signals of the
1
3
corresponding С nuclei in the heteronuclear spectra
1
13
[
Н– С] HSQC. As seen from the data of Table 1, the
δН value for the methyl groups in the cis-position in
H C
CH3
3
1
3
2
cis
trans
N
X
_
I V
H C
2
HB
a
b
X = Ph (I), CH Ph (II),
(III),
HA
N=CH (CH ) (IV), OH (V).
2 3 2
2
HX
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 8 2013

1120
AFONIN et al.
perimental trend (Table 1). The calculation also predicts
the increase in the chemical shift of the carbon atom of
the methyl group by 9.1 ppm and the growth of the cor-
responding direct coupling constant С– С by 9.9 Hz
in going from trans- to cis-configuration of ketimine I
drous ether [27] using feshly calcined molecular sieves
Wolfen-Zeosorb 4 A (Kugelform). After keeping the
reaction mixture at 10°С for 5 days the yield of imine I
was 70%. The physical constants were in agreement with
published data [27].
1
3
13
(
Table 2. 3). The quantum-chemical calculations of δ for
C
N-(Isopropylidene)benzylamine (II) was obtained
by the method similar to that used for the synthesis of
imine III [28] in 45% yield. The physical constants and
elemental analysis data corresponded to those published
in [29], where this compound was synthesized using
Bentonite as the dehydrating agent.
N-(Isopropylidene)allylamine (III) was synthe-
sized by procedure [28]. The physical constants were in
agreement with published data.
ketimines II, III give analogous results: The theoretical
values of the chemical shifts for the trans-СН group
are by 13.5 and 14.7 ppm respectively less than for the
cis-СН group (Tables 1, 2)
3
3
H C
CH3
3
Y
N
.
ACKNOWLEDGMENTS
The stereochemical dependence of parameters δ and
1J(C,C) in ketimines I–III, acetone azine (IV) and acetone
oxime (V) obeys the general regularity. In all compounds
the protons and carbon atoms of the trans-СН group are
C
The study was carried out under the financial support
of the Russian Foundation for Basic Research (grant no.
1-03-00423-а).
3
1
1
more shielded than in the cis-СН group, and J(C,C) is
3
larger in the latter case. Therefore the values of the direct
REFERENCES
1
3
13
13
coupling constants С– С and the С chemical shifts
can be used for the configuration assignment in a wider
1
2
3
. Comprehensive Organic Chemistry, Barton, D. and Ol-
lis, W.D., Eds., Oxford: Pergamon, 1979, vol. 3.
. Lang, X., Ma, W., Zhao, Y., Chen, C., and Ji, H., Zhao, J.
Chem. Eur. J., 2012, vol. 18, p. 2624.
. Neochoritis, C.G., Zarganes-Tzitzikas, T., Tsoleridis,
C.A., Stephanidou-Stephanatou, J., Kontogiorgis, C.A.,
Hadjipavlou-Litina, D.J., and Choli-Papadopoulou, T., Eur.
J. Med. Chem., 2011, vol. 46, p. 297.
1
series of Schiff bases. The larger values of δ and J(C,C)
C
of the α-carbon of the substituent may be attributed to
the isomer of the Schiff base where this substituent has
the cis-orientation with respect of the unshared electron
pair of the nitrogen atom of the >C=N– group, whereas
the smaller values belong to the isomer with the trans-
orientation of the substituent. The values of δ may be
Н
used in the configuration analysis with a considerable
caution for they are essentially affected by the magnetic
anisotropy of the substituents.
4. Texier-Boullet, F., Synthesis, 1985, p. 679.
5
. Smith, S.O., Myers, A.B., Pardoen, J.A., Winkel, C., Mul-
der, P.P., Lugtenburg, J., and Mathies, R., Proc. Natl. Acad.
Sci. USA., 1984, vol. 81, p. 2055.
6
7
. Fodor, S.P., Bogomolni, R.A., and Mathies, R.A., Biochem.,
EXPERIMENTAL
1
987, vol. 26, p. 6775.
. Deng, H., Manor, D., Weng, G., Rath, P., Koutalos, Y.,
Ebrey, T., Gebhard, R., Lugtenburg, J., and Tsuda, M.,
Callender, R.H. Photochem. Photobiol., 1991, vol. 54,
p. 1001.
1Н and 13С NMR spectra of ketimines I–III were
registered on a spectrometer Bruker Avance 400 (400.13
and 101.6 МHz respectively).
Compounds I–III are liquids easily hydrolyzed in the
presence of moisture. The NMR spectra of compounds II,
8. Livnah, N. and Sheves, M., Biochem., 1993, vol. 32 p. 7223.
9
. Deng, H., Huan, L., Groesbeek, M., Lugtenburg, L., and
Callender, R.H., J. Phys. Chem., 1994, vol. 98, p. 4776.
III were recorded from 5% solutions in СDCl , of com-
3
1
0. Farrar, M.R., Lakshmi, K.V., Smith, S.O., Brown, R.S.,
Raap, J., Lugtenburg, J., Griffin, R.G., and Herzfeld, J.,
Biophys. J., 1993, vol. 65, p. 310.
pound I, from neat liquid. The direct coupling constants
13
13
С– С for the latter compound were measured by the
satellite signals at the natural abundance of the magneti-
11. Lakshmi, K.V., Auger, M., Raap, J., Lugtenburg, J.,
1
3
cally active isotope С. Internal reference HMDS.
Griffin, R.G., and Herzfeld, J., J. Am. Chem. Soc., 1993,
vol. 115, p. 8515.
N-(Isopropylidene)phenylamine (I) was synthesized
from dry acetone and freshly distilled aniline in anhy-
12. Pfleger, N., Lorch, M., Woerner, A.C., Shastri, S., and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 8 2013

APPLICATION OF CHEMICAL SHIFTS
1121
Glaubitz, C., J. Biomol. NMR, 2008, vol. 40, p. 15.
3. Rozwadowski, Z., Ann. Rep. NMR, Spectr., 2011, vol. 74,
p. 125.
4. Perona, A., Sanz, D., Claramunt, R.M., and Elguero, J.,
Molecules, 2006, vol. 11, p. 453.
5. Afonin,A.V., Pavlov, D.V., Ushakov, I.A., Schmidt, E.Yu.,
and Mikhaleva, A.I., Magn. Res. Chem., 2009, vol. 47,
p. 879.
6. Afonin,A.V., Ushakov, I.A., Pavlov, D.V., Ivanov,A.V., and
Mikhaleva, A.I., Magn. Res. Chem., 2010, vol. 48, p. 685.
7. Afonin, A.V., Pavlov, D.V., Albanov, A.I., Levanova, E.P.,
and Levkovskaya, G.G., Magn. Res. Chem., 2011, vol. 49,
p. 740.
Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V.,
Mennucci, B., Peters-son, G.A., Nakatsuji, H., Carica-
to, M., Li, X., Hratchian, H.P., Izmaylov, A.F., Bloino, J.,
Zheng, G., Sonnenberg, J.L., Hada, M., Ehara, M.,
Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Naka-
jima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Mont-
gomery, J.A. Jr., , Peralta, J.E., Ogliaro, F., Bearpark, M.,
Heyd, J.J., Brothers, E., Kudin, K.N., Staroverov, V.N.,
Kobayashi, R., Normand, J., Raghavachari, K., Ren-
dell, A., Burant, J.C., Iyengar, S.S., Tomasi, J., Cossi, M.,
Rega, N., Millam, J.M., Klene, M., Knox, J.E., Cross,
J.B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R.,
Stratmann, R.E., Yazyev, O., Austin, A. J., Cammi, R., Po-
melli, C., Ochterski, J.W., Martin, R.L., Morokuma, K., Za-
krzewski, V.G., Voth, G.A., Salvador, P., Dannenberg, J.J.,
Dapprich, S., Daniels, A.D., Farkas, O., Foresman, J.B.,
Ortiz, J.V., Cioslowski, J., and Fox, D.J., GAUSSIAN 2009,
Pittsburg: Gaussian, Inc., 2009.
1
1
1
1
1
1
1
8. Afonin,A.V., Pavlov, D.V., Ushakov, I.A., and Keiko, N.A.,
Magn. Res. Chem., 2012, vol. 50, p. 502.
9. Afonin, A.V., Pavlov, D.V., Ushakov, I.A., Levanova, E.P.,
and Levkovskaya, G.G., Zh. Org. Khim., 2012, vol. 48,
p. 362.
2
0. Afonin, A.V., Ushakov, I.A., Pavlov, D.V., Levanova, E.P.,
Levkovskaya, G.G., Izv. Akad. Nauk, Ser. Khim., 2012,
p. 1108.
25. Ditchfield, R., Mol. Phys., 1974, vol. 27, p. 789.
26. Peralta, J.E., Barone, V., Contreras, R.H., Zaccari, D.G.,
and Snyder, J.P., J. Am. Chem. Soc., 2001, vol. 23, p. 9162.
2
2
2
7. Tsuchimoto, M., Nishimura, S., and Iwamura, H., Bull.
Chem. Soc. Jpn., 1973, vol. 46, p. 675.
8. Norton, D.G.H., Frank, C.D., Lloyd, J.M., and Seaver,A.B.,
J. Org. Chem., 1954, vol. 9, p. 1054.
9. Saoudi, A., Benguedach, A., Benhaoua, H., Synth. Com-
mun., 1995, vol. 25, p. 2349.
2
2
1. Krivdin, L.B., Kalabin, G.A., Nesterenko, R.N., and Tro-
fimov, B.A., Zh. Org. Khim., 1984, vol. 20, p. 2477.
2. Krivdin, L.B., Kalabin, G.A., Nesterenko, R.N., and Tro-
fimov, B.A., Tetrahedron Lett., 1984, vol. 25, p. 4817.
3. Afonin, A.V., Zh. Org. Khim., 2011, vol. 47, p. 499.
4. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E.,
2
2
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