Application of theoretically computed chemical shifts to structure determination of novel heterocyclic compounds

Article abstract of DOI:10.1016/j.molstruc.2006.01.008

Combined use of 2D NMR correlation methods (¹H-¹³C and ¹H-¹⁵N 2D HMBC) and the DFT-GIAO chemical shift calculations allows unequivocal determination of structure for novel quinoxaline. Such interplay of experime

Full text of DOI:10.1016/j.molstruc.2006.01.008

Journal of Molecular Structure 791 (2006) 77–81
www.elsevier.com/locate/molstruc
Application of theoretically computed chemical shifts to structure
determination of novel heterocyclic compounds
Alsu Balandina, Dina Saifina, Vakhid Mamedov, Shamil Latypov
*
NMR Spectroscopy Laboratory, Institute of Organic and Physical Chemistry, Arbuzov Street 8, Kazan, Tatarstan 420088, Russia Federation
Received 27 November 2005; received in revised form 11 January 2006; accepted 16 January 2006
Available online 2 March 2006
Abstract
1
13
1
15
Combined use of 2D NMR correlation methods ( H– C and H– N 2D HMBC) and the DFT-GIAO chemical shift calculations allows
unequivocal determination of structure for novel quinoxaline. Such interplay of experiment and theory is really reliable and convenient way for
structure elucidation of complex heterocycles.
q 2006 Elsevier B.V. All rights reserved.
1
13
Keywords: 2D NMR; H, C and N chemical shifts; DFT-GIAO chemical shifts; Structure elucidation; Quinoxalines
15
1
. Introduction
Here, we show how combined use of modern 2D NMR
methods and non-empirical chemical shift (CS) calculations
provides simple and reliable way to recover overall structure of
new heterocyclic compound of practical interest.
The developments of NMR equipment and powerful
multi-dimensional correlation NMR techniques have opened
a direct way for the structure elucidation of organic
compounds in solution [1]. Nevertheless, particularly in
the field of natural products and heterocyclic chemistry,
when there are several non-magnetic nuclei in a molecular
skeleton, these methods can be used to establish the
structure of the fragments only. In such cases, one needs
reliable rules to combine experimentally derived fragments
into molecule as whole [2]. Therefore, often NMR spectro-
scopists undergo an arduous intellectual journey of ‘puzzle
solving’ before they finally find correct structure of an
unknown molecule.
2. Experimental
2.1. Synthesis of compounds
2.1.1. Preparation of 3-phenylbromeacetylquinoxaline-2(1H)
one (2)
To the suspension of 0.2 g (0.75 mmol) of 3-phenylace-
tylquinoxaline-2(1H)one and 0.062 g (0.75 mmol) of sodium
acetate in 10 mL acetic acid was added slowly 0.04 mL
(0.75 mmol) of bromine in 5 mL acetic acid. The mixture
An application of theoretically computed chemical shifts
to link these fragments (‘to solve puzzle’) is very
challenging although it has not yet become routine in
practical applications [3]. It has been recently demonstrated
was stirred during 3 h. After cooling, the reaction mixture
was poured into water (30 mL). The precipitated product
was collected by filtration and washed with H O (2!
2
1
0 mL), dried to give the yellow crystalline compound (2),
1
1
3
that predicted chemical shifts (i.e. C) are accurate within a
very few parts per million for molecules in solution that
include a wide variety of functional groups and confor-
mations [4]. The predictions also can be achieved at modest
computational cost.
yield 75%, mp. O310 8C (decom.); H NMR (CDCl3,
4
00 MHz, 25 8C): dZ7.96 (1H, d, JZ8.2 Hz, H-5), 7.68
0
(1H, dd, JZ8.2, 7.5 Hz, H-7), 7.59 (2H, d, JZ6.9 Hz, H-2 ,
0
H-6 ), 7.50 (1H, d, JZ8.2 Hz, H-8), 7.44 (1H, dd, JZ7.8,
0 0 0
7.5 Hz, H-6), 7.35 (3H, m, H-3 , H-4 , H-5 ), 6.93 (1H, s,
CH); IR, n, cm
K1
(potassium bromide) (Vector-22
Bruker)): 528, 552, 560, 593, 701, 732, 759, 960, 1122,
(
*
Corresponding author. Tel.: C7 843 2727484; fax: C7 843 2732253.
E-mail address: lsk@iopc.knc.ru (S. Latypov).
1
2
130, 1141, 1346, 1465, 1492, 1540, 1607, 1654, 1716,
725, 3084, 3475, 3611. C H BrN O found, %: C 56.21,
1
6
11
2 2
H 3.35, Br 23.42, N 8.10. Calculated, %: C 56.00, H 3.23,
Br 23.28, N 8.16.
0022-2860/$ - see front matter q 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2006.01.008

78
A. Balandina et al. / Journal of Molecular Structure 791 (2006) 77–81
(
C-8a), 138.29 (C-9a), 138.16 (C-4a), 134.68 (C-1), 128.80 (C-
0
0 0 0
1
), 128.76(C-4 ), 128.73(C-3 , C-5 ), 128.68(C-6), 128.07(C-5,
C
0
0
C-8), 128.02 (C-7), 124.81 (C-2 , C-6 ); m/zZ(262)M ; IR, n,
cm (neat) (Vector-22 (Bruker)): 656, 684, 758, 769, 1060,
K1
1
1
119, 1133, 1164, 1224, 1289, 1307, 1325, 1410, 1443, 1513,
566, 1630, 1665, 1720, 2629. C H N O found, %: C 73.04, H
1
6 10 2 2
Scheme 1.
3.64, N 10.42. Calculated, %: C 73.27, H 3.84, N 10.68.
2.2. NMR spectroscopy
All NMR experiments were performed in dilute DMSO
solutions at 50 8C with a Bruker AVANCE-600 spectrometer
equippedwitha5 mm diameterbroad bandprobehead workingat
1
13
15
6
00,000 MHz in H, 150.864 MHzin Cand60.796 MHz in N
experiments. CSs are reported on the d (ppm) scale and are
1
13
15
relative to the residual H and C signal of DMSO-d6. N CSs
1
were referenced to the external of CD CN. Assignment of the H
3
1
3
and C NMR spectra of the title compounds was accomplished
by DEPT, 2D COSYGP, HSQC, HMBC experiments. Related
1D and 2D NMR spectra can be obtained in supporting materials.
2.3. Computational methods
1
13
Fig. 1. COSY (black arrows), HSQC (gray) and principal HMBC ( H– C—
1 15
gray and H– N—dotted arrows) correlations for 3.
CSs were determined within the DFT framework using a
hybrid exchange-correlation functional, B3LYP, at the
-31G(d) level as implemented in Gaussian 98 [5]. Full
geometry optimizations were done at the ab initio RHF/6-31G
2.1.2. Preparation of 2-phenyl-3-hydroxyfuro[2,3-b]
quinoxaline (3)
6
The filtrate obtained above by dilution with water was kept
overnight in at room temperature and the precipitate was
1
13
level. All data were referred to TMS ( H and C) and NH3
15
(
N) CSs that were calculated in the same conditions.
collected by filtration and dried to give the white crystalline
1
compound (3), yield 20%, mp Z252–253 8C; H NMR (DMSO,
.
3. Results and discussion
6
H-2 , H-6 ), 8.09(1H, m, H-5), 7.83(2H, m, H-7), 7.82(2H, m, H-
00 MHz, 50 8C): dZ8.21 (1H, m, H-8), 8.15 (2H, d, JZ6.2 Hz,
0
0
The current study was initiated by attempts to find new drug
0 0
13
6
6
1
), 7.59 (2H, dd, JZ6.2, 3.1 Hz, H-3 , H-5 ), 7.46 (1H, ddt, JZ
.2, 3.1 Hz, H-4 ), 3.29 (br, OH); C NMR (DMSO,
50.86 MHz, 50 8C): dZ151.04 (C-3), 144.42 (C-2), 140.92
candidates among the derivatives of 3-phenylacetylquinoxalin-
-one (1) [6]. In the reaction of 1, besides the main product—3-
phenylbromacetylquinoxalin-2(1H)-ones (2)—the novel
0
2
1
3
15
Fig. 2. (a) Experimental data for three with CSs (in ppm) of C and N (bold); (b) hypothetical structural isomers of three with calculated CSs of C and N (bold).
13
15

A. Balandina et al. / Journal of Molecular Structure 791 (2006) 77–81
79
product (3) was always obtained (Scheme 1). Unfortunately,
1
GIAO-calculated CS values of optimized trial structures of
13
3 (Fig. 2b) were compared versus experimental C NMR data.
13
H and C NMR spectra could not be directly ascribed to
1
3
reaction products we expected.
1
H spectrum of 3 consists of several signals of aromatic
The GIAO method underestimates ( C) CSs, particularly in
low field region therefore the shifts might need scaling in order
to provide quantitative match with experimental shifts
protons and broadened line at d 3.29. Two groups of protons of
benzo moieties and phenyl group uniquely stand out in the 2D
COSY spectrum (Fig. 1).
(3m,4b,g). However, in practice, it is important that the
relative order of shifts could be predicted accurately which can
be characterized by correlation coefficient between theoretical
and experimental CS. Therefore, least-squares linear fitting
1
3
The C NMR CSs of all hydrogenated carbons could be
assigned unambiguously by the 2D HSQC spectrum. The most
important are 2D HMBC correlations, which allow to assign
resonance of some quaternary carbons and to establish the
structures of two molecular parts (Fig. 1). Namely, there are
correlations between the protons of benzo moieties at d 8.09
and d 7.83 and the carbon resonance at d 140.92; the protons at
2
parameters (R or rms) of correlation plots between computed
(without scaling) and experimental CS values can be employed
to discriminate among the structural hypotheses [9]. As
13
example correlation of C CSs is shown in Fig. 3 and the
results of the linear regression analysis comparing experimen-
tal shifts to GIAO CSs are summarized in Table 1.
Analysis of these data unequivocally demonstrated that only
8
protons at 7.59 (H-3 , H-5 ) and the carbon resonance at d
.21 and d 7.82 and the carbon resonance at d 138.16; the
0
0
0
0
0
1
28.80 (C-1 ); the protons at 8.15 (H-2 , H-6 ) and the carbon
13
for the C isomer predicted C CSs correlate well with
2
experimental ones (Fig. 3). Only for the isomer C the R values
resonance at d 144.42. In addition, there are three quaternary
carbons at d 151.04, 138.29 and 134.68, which have no HMBC
correlations to any protons, and therefore these resonance
cannot be assigned and there is no experimental (NMR) ground
to link these three carbons to above fragments.
are in the range of 0.93 (for skeletal carbons)—0.97 (for all
carbons). On the other hand, with regard to other isomers, the
calculated values obviously do not agree with experimental
results (Fig. 3), where the correlation coefficients are
In addition, the structure of benzo fragment was extended to
two nitrogen’s from the analysis N–H HMBC correlations [7]:
there are cross-peaks between the proton signal of benzo
moieties at d 8.21 and the nitrogen resonance at d 300.18; the
proton signal at d 8.09 and the nitrogen resonance at d 261.11
(
Fig. 1).
Thus, from extensive spectroscopic investigation two
fragments (benzo moiety bonded to nitrogen atoms and phenyl
fragment) were surely revealed (Fig. 1) by use of 2D
correlation experiments.
Besides, there may be one NH or OH protons, which can be
masked (or in exchange) by residual water in DMSO. The mass
spectrometry (MS) data indicated that the sample is homo-
C$
geneous with molecular weight of m/zZ262(M ). Taking
into account elemental analysis its molecular formula was
derived to be C H N O .
1
6 10 2 2
Chemically meaningful structural isomers were generated
by combination of these two experimentally derived fragments
bound via moieties possessing two oxygen, one proton and
three quaternary carbons and then were used as trial structures
for further analysis (Fig. 2). Thus, finally to establish correct
structure of 3 one needs a safe and reliable way to choose
among the hypothetical ones. Until now, no CS information
was used to recover the structure of fragments that were
derived from HMBC connectivity only.
It has been shown recently that DFT-GIAO calculations of
1
3
NMR C CSs can provide valid support in interpreting
1
3
experimental C NMR data of unknown species, and hence in
resolving structural controversies. Thus, it seems, that having
1
13
15
NMR spectra ( H, C and N), one is able to choose correctly
one structure from possible variety of trial structural isomers
obtained from a molecular formula [4,8]. Therefore, we applied
1
such approach to establish real structure of 3. H CSs are less
1
3
15
1
3
sensitive to skeletal structure therefore only C and N CSs
were analyzed in details.
Fig. 3. Correlation of calculated versus experimental C CSs (C-1, C-2, C-3a,
0
C-4a, C-5, C-8, C-8a, C-9a, C-1 atoms) for isomers A–F (shown on Fig. 2).

80
A. Balandina et al. / Journal of Molecular Structure 791 (2006) 77–81
Table 1
utility of CambridgeSoft’s ChemDraw Program [10] gives very
13
poor prediction of C CSs and correlation coefficients in all
Linear correlation coefficients of experimental vs calculated (GIAO
1
RB3LYP/6-31G(d)//RHF/6-31G)
3
2
CSs (R ), root-mean-square
C
cases (for wrong and right structures) do not exceed 0.57 and
rms is higher than 10.
errors (rms), slope (a), standard deviations (sd) and mean absolute deviations
P
ðMADZ ½jd Kdcalcdjꢀ=nÞ for the isomers A–F
exp
It is worth mentioning that above used non-empirical
calculations of CS are very cheap in the sense of computational
costs and most of the researchers can run them easily on their
desk computers (3–5 h per one isomer on Pentium 4 CPU
2
R
Structure
rms
a
sd
MAD
a
b
c
A
0.4586
11.62
16.22
19.90
13.80
20.03
19.17
1.16
1.39
2.66
3.37
0.76
0.94
0.92
0.95
0.93
1.50
1.45
2.13
1.46
1.33
1.49
2.33
0.30
0.91
2.94
12.06
17.77
21.79
14.32
21.94
21.00
1.20
11.39
15.63
15.55
12.93
18.11
14.28
7.03
0
0
.5150
.5709
2.80 GHz 512 Mb RAM).
B
C
D
E
F
0.1458
0
0
.0574
.0605
4. Conclusion
0.9768
0
0
.9345
.3628
1.35
1.48
7.30
8.59
The structure of furo[2,3-b]quinoxaline (3) obtained in the
10.85
20.56
31.17
32.16
8.89
11.88
21.33
34.14
35.23
9.22
reaction of 3-phenylacetylquinoxaline-2(1H)one and bromine
in acetic acid in the presence of sodium acetate was
unambiguously determined.
0.2231
13.06
22.70
25.41
8.92
0
0
.1196
.0548
0.5744
Combined use of modern multi-dimensional NMR tech-
niques and non-empirical calculations of CSs was shown to be
a very efficient and reliable way to elucidate chemical structure
of novel compounds in reasonable time.
0
0
.3122
.5509
11.94
13.18
21.14
31.02
34.28
13.08
14.44
21.94
33.98
37.55
10.54
16.11
13.10
22.40
26.84
0.0115
0
0
.0235
.1835
a
b
c
13
Acknowledgements
All C.
Only skeletal carbons [9]: C-1, C-2, C-3a, C-4a, C-8a, C-9a.
Estimated according to additive scheme (CambridgeSoft’s ChemDraw
This study was financially supported by the Russian
Foundation for Basic Research (Project no. 03-03-32865, no.
13
Program, quaternary C: C-1, C-2, C-3a, C-4a, C-8a, C-9a).
05-03-32558-a).
essentially less (0.52–0.57) or even worse (Table 1). The rms
value for the C isomer is also by an order of magnitude smaller
than that for other hypotheses.
Supplementary Data
1
5
Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.molstruc.2006.01.008
Moreover, N CSs are also in full agreement with this
conclusion. As one can see from diagrams of mismatches
between experimental and calculated CSs for the hypothetical
structures (Fig. 4), only for the C isomer reasonably small
deviations are observed while for other structures the
differences were large.
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[9] Basically we stressed our attention on the analyses of CSs of only
‘skeletal’ nuclei because: on the one hand the CSs of substituents have
basically to reflect particularities of substituents themselves and, therefore
their correlation can hardly be characteristic of the backbone structure; on
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