The anisotropic effect of functional groups in 1H NMR spectra is the molecular response property of spatial nucleus independent chemical shifts (NICS) - Conformational equilibria of exo/endo tetrahydrodicyclopentadiene derivatives

Article abstract of DOI:10.1039/c0ob00356e

The inversion of the flexible five-membered ring in tetrahydrodicyclopentadiene (TH-DCPD) derivatives remains fast on the NMR timescale even at 103 K. Since the intramolecular exchange process could not be sufficiently slowed for spectroscopic evaluation, the conformational equilibrium is thus inaccessible by dynamic NMR. Fortunately, the spatial magnetic properties of the aryl and carbonyl groups attached to the DCPD skeleton can be employed in order to evaluate the conformational state of the system. In this context, the anisotropic effects of the functional groups in the ¹H NMR spectra prove to be the molecular response property of spatial nucleus independent chemical shifts (NICS).

Full text of DOI:10.1039/c0ob00356e

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PAPER
The anisotropic effect of functional groups in 1H NMR spectra is the
molecular response property of spatial nucleus independent chemical shifts
(NICS)—Conformational equilibria of exo/endo tetrahydrodicyclopentadiene
derivatives
Erich Kleinpeter,* Anica La¨mmermann and Heiner Ku¨hn
Received 30th June 2010, Accepted 25th October 2010
DOI: 10.1039/c0ob00356e
The inversion of the flexible five-membered ring in tetrahydrodicyclopentadiene (TH-DCPD)
derivatives remains fast on the NMR timescale even at 103 K. Since the intramolecular exchange
process could not be sufficiently slowed for spectroscopic evaluation, the conformational equilibrium is
thus inaccessible by dynamic NMR. Fortunately, the spatial magnetic properties of the aryl and
carbonyl groups attached to the DCPD skeleton can be employed in order to evaluate the
conformational state of the system. In this context, the anisotropic effects of the functional groups in
the 1H NMR spectra prove to be the molecular response property of spatial nucleus independent
chemical shifts (NICS).
to unequivocally assign preferred conformers even if the basic
Introduction
dynamic process is still too fast on the NMR timescale. This leads
The spatial magnetic properties of molecules can be determined
to the conclusion that the anisotropic effects of functional groups
1
via through-space NMR shieldings (TSNMRS) and visualized as
on the signals in H NMR spectra are the molecular response
iso-chemical-shielding surfaces (ICSS).1 This methodology1 has
property of NICS.
been successfully applied to depict and, moreover, to quantify the
Our approach has also been employed to locate the precise
anisotropic effects of functional groups and ring-current effects
position of ligands (inhibitors) in the binding pocket of enzymes
of aryl moieties on proton NMR chemical shifts. TSNMRS have
employing the ring-current effects of the aromatic moieties of
also been employed for stereochemical assignment and to examine
amino acid residues proximate to the ligand in the binding
the diastereoisomerism of various structures.2–14 Furthermore,
anisotropic and ring-current effects, thus evaluated with respect
to their influence on the proton chemical shifts, can be separated
and distinguished from steric compression effects in cases where
the latter contribute considerably to 1H chemical shift differences
in stereoisomers.15,16 Finally, TSNMRS have also been employed
to qualify the (anti)aromaticity17 of push–pull compounds18
and to evaluate quinonoid vs. benzenoid,19 captodative20 and
coordinative21 organic and inorganic compounds.
Of significant note though, there have been some recent
developments of the nucleus independent chemical shifts (NICS)
index22 demonstrating that only the NICS(1)zz component can
be rigorously used to quantify aromaticity,23 whilst averaged
NICS have proven to be generally unsuitable for the quantitative
evaluation of aromaticity.24 In addition, it should be pointed out
that there are still serious reservations with regards to qualifying
molecular response properties by unobservable quantities such
as NICS.24a However, in this work we will present for the first
time a definitive example of the application of spatial NICS
pocket.4 For the same purpose, complexation induced shifts (CIS)
of ligands containing aromatic rings were used by Hunter and
Packer25 and McCoy and Wyss;26 based on this idea the latter wrote
a computer program Jsurf .26 This method was adopted by Hunter
et al.,27 incorporated into a three stage procedure and developed
into a robust and flexible procedure of wide applicability, although
limited to aromatic ligands.
Similar approaches to estimate TSNMRS have been published
by Alkorta and Elguero,28 and Martin et al.29 In both cases,
shieldings of similar size and direction, comparable with the results
of our approach1 and the classical model of Bovey and Johnson30
and Haigh and Mallion,31,32 were obtained.
Results and discussion
Chemical syntheses and NMR spectra
Tetrahydrodicyclopentadiene (TH-DCPD) derivatives 1a, 2a, 4b,c,
6b,c, 7a and 8a (Scheme 1) were able to be synthesized and isolated.
These compounds, along with other stereoisomers of 1–8 to
complete sets of structures, were also subjected to computational
examinations (vide infra). The parent compounds, exo- and
Universita¨t Potsdam, Institut fu¨r Chemie, Karl-Liebknecht-Str. 24-25,
D-14476, Potsdam (Golm), Germany. E-mail: ekleinp@uni-potsdam.de;
Fax: +49-331-977-5064; Tel: +49-331-977-5210
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Scheme 1 Tetrahydrodicyclopentadiene (DCPD) derivatives 1–8.
endo-tetrahydrodicyclopentadiene 1 and 2 were synthesized by
catalytic hydrogenation of the separated DCPD isomers which
provided initially the 9,10-dihydro derivatives quantitatively, prior
to further hydrogenation to yield compounds 1 and 2.33a,b Pre-
cursor compounds for the mono- and diketones studied were the
exo/endo-1,2-DH-DCPD which were produced from exo/endo-
DCPD via 3-step (exo)34a,b and 5-step syntheses (endo).34c,d
(endo)Mono- (4b) and (endo)diketo derivatives (6b) were obtained
from exo-DH-DCPD by reaction with t-butyl hypochlorite in
acetic acid, saponification of the acetate and oxidation of the
intermediate alcohol (cf. Scheme 2); the monoketone 4b, thus
obtained, was further oxidized with SeO2 to the diketone 6b. The
corresponding bromo analogues 4c and 6c were obtained by the
same procedure but using N-bromo succinimide instead of t-butyl
hypochlorite.
The precursor compound 3a for the quinoxaline derivative 7a
was synthesized by hydration of endo-DCPD with diluted sulfuric
acid, hydrogenation and finally oxidation;35 further oxidation with
SeO2 delivered the diketone 5a (unstable) which quenched with
o-phenylene diamine to 7a (cf. Scheme 3).
The exo/endo configurations of DCPD derivatives 1–8 were
assigned by 1H36 and 13C NMR spectroscopy.37 The detailed signal
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Scheme 2 Synthesis of 7-chloro(bromo)-TH-DCPD-9-ones (4), -diones (6) and the quinoxaline derivative (8).
Scheme 3 Synthesis of quinoxaline derivative 7a.
assignments of both nuclei were effected by COSY, HSQC and
HMBC experiments. For the proton NMR spectra of monoke-
tones 3 and 4, due to severe overlap of several signals, HSQC
was ineffective for assignment purposes in the relevant region but
HSQC-TOCSY experiments ensured the full assignment for all 1H
and 13C NMR signals in these cases. The experimental chemical
shifts are presented in Tables 1 and 2.
Theoretical calculations
The structures of 1–8 in Scheme 1 were computed and the geome-
tries fully optimized using the Gaussian0338 program employing ab
initio calculations at the MP2/6-311G** level.39–41 The exo/syn,
exo/anti, endo/syn and endo/anti conformers (cf. Scheme 4)
of 1–8 were evaluated and, in order to describe the dynamic
process of five-membered ring inversion, the transition states
were characterized by force constants as stationary points on the
potential energy surface. NMR parameters were calculated using
the GIAO method42 at the B3LYP/6-31G(d,p) level of theory by
subtracting the shieldings of the protons and carbon atoms in 1–8
from tetramethylsilane (TMS) used as a reference and calculated at
the same level of theory; the PCM solvent model43 was employed
to consider CDCl3 as the solvent. Computed chemical shifts are
also given in Tables 1 and 2 (vide supra).
Scheme 4 Conformational equilibrium of DCPD derivatives.
CDCl3 were correlated with the computed d values [cf. Fig. 1 for
d(13C)]. The excellent correlation obtained was strong evidence for
accurately computed structures of the compounds and, because
of better correlations in the case of the endo/syn conformers in
comparison to the endo/anti conformers (in the case of the exo
isomers, only the exo/anti conformer was considered), the first
Experimental 13C NMR chemical shifts of TH-DCPD deriva-
tives 1a, 2a, 4b,c, 6b,c, 7a and 8a (Scheme 1) measured in
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Table 1 1H Chemical shifts d/ppm (experimental and computed at the DFT level of theory) of the DCPD derivatives 1–8
H-9 eq
H-9 ax
H-8
H-4
H-5
H-6
H-7 syn
compound
exp
calc
exp
calc
exp
calc
exp
calc
exp
calc
exp
calc
exp
calc
8a
7a
6b
6c
4b
4c
2a
1a
—
—
—
—
2.56
2.62
1.27
1.45
—
—
—
—
2.65
2.77
1.38
1.52
—
—
—
—
2.16
2.16
1.42
1.05
—
—
—
—
2.03
2.03
1.58
1.10
3.43
3.29
3.29
3.34
2.71
2.73
2.1
3.26
3.12
2.81
2.87
2.38
2.44
2.07
1.93
3.11
2.27
3.02
3.02
2.72
2.76
2.33
1.75
3.05
2.25
2.76
2.79
2.52
2.55
2.39
1.85
3.11
2.27
3.02
3.02
2.72
2.76
2.33
1.75
3.05
2.25
2.76
2.79
2.54
2.57
2.39
1.85
3.43
3.29
3.29
3.34
2.70
2.72
2.10
1.93
3.26
3.12
2.81
2.87
2.33
2.42
2.07
1.93
2.17
1.98
Cl
Br
Cl
Br
1.37
0.88
2.01
1.85
Cl
Br
Cl
Br
1.42
0.95
1.93
H-7 anti
H-1 anti
H-1 syn
H-2 anti
H-2 syn
H-3 anti
H-3 syn
compound
exp
calc
exp
calc
exp
calc
exp
calc
exp
calc
exp
calc
exp
calc
8a
7a
6b
6c
4b
4c
2a
1a
2.12
2.17
4.55
4.38
4.28
4.27
1.51
1.31
1.89
2.18
4.05
4.16
3.85
4.00
1.50
1.50
1.52
2.07
1.69
1.69
1.58
2.05
1.70
1.71
1.80
1.80
1.52
1.06
1.18
1.29
1.46
1.48
1.39
1.40
1.49
1.82
1.38
1.35
1.50
1.51
1.47
1.48
1.74
1.87
1.14
1.94
1.62
0.64
1.92
1.44
1.44
1.49
1.50
1.60
1.61
-0.42
1.51
1.17
-1.88
1.63
1.34
1.36
1.56
1.58
1.63
1.27
1.52
2.07
1.69
1.58
2.05
1.70
1.71
1.70
1.71
1.52
1.06
1.18
1.29
1.46
1.38
1.35
1.50
1.51
1.60
1.62
1.74
1.87
1.64
1.18
1.69
1.48
a
b
b
b
1.66
a
a
a
a
a
1.43
0.92
1.57
1.59
1.61
1.13
1.43
0.92
1.49
1.82
a Range of d, 1.75–1.50 ppm. b Range of d, 1.80–1.47 ppm.
Table 2 13C chemical shifts d/ppm (experimental and computed at the DFT level of theory) of the DCPD derivatives 1–8
C-1
exp.
C-2
exp.
C-3
exp.
C-4
exp.
C-5
compound
comp.
comp.
comp.
comp.
exp.
comp.
8a
7a
6b
6c
4b
4c
2a
1a
27.88
31.56
28.35
28.41
28.26
28.38
26.95
32.43
30.29
33.57
30.44
30.60
30.04
30.10
29.94
34.31
26.78
29.14
27.03
27.06
27.37
27.66
28.77
27.24
27.45
31.89
28.97
28.92
29.51
29.39
30.51
29.48
27.88
31.56
28.35
28.41
27.63
27.66
26.95
32.43
30.29
33.58
30.44
30.60
30.48
30.65
29.94
34.31
45.91
45.56
43.57
44.50
41.33
41.51
45.53
48.22
48.79
48.87
46.52
47.26
43.75
44.14
47.27
50.16
45.91
45.56
43.57
44.50
43.06
43.90
45.53
48.22
48.79
48.87
46.51
47.26
46.24
46.94
47.27
50.16
C-6
exp.
C-7
exp.
C-8
exp.
C-9
exp.
C-10
exp.
compound
comp.
comp.
comp.
comp.
comp.
8a
7a
6b
6c
4b
4c
2a
1a
48.60
48.28
61.12
60.99
62.26
62.79
41.57
40.68
49.97
49.40
62.07
62.54
62.89
63.89
44.32
42.47
48.12
38.54
57.11
45.42
64.21
54.65
43.30
32.08
47.74
40.65
61.51
58.46
67.29
65.28
43.27
33.42
48.60
48.28
61.12
60.99
45.33
45.45
41.57
40.68
49.97
49.41
62.07
62.54
47.59
48.20
44.32
42.47
162.68
164.85
199.66
199.33
36.58
37.50
23.06
158.02
160.33
197.77
197.21
37.78
38.29
26.16
162.68
164.85
199.66
199.33
213.80
213.72
23.06
158.02
160.33
197.77
197.21
205.13
205.11
26.16
28.77
31.48
28.77
31.48
hint for these endo/syn structures as the preferred, or at least
higher populated conformers, was obtained. The corresponding
correlations of proton chemical shifts are not given because of
significant signal overlap in the experimental 1H NMR spectra.
To calculate the NICS,44 ghost atoms were placed within a
were analyzed and visualized by SYBYL 7.3 molecular modeling
software;45 different ICSS of -0.1 ppm (red) deshielding and 5 ppm
(blue), 2 ppm (cyan), 1 ppm (green-blue), 0.5 ppm (green) and 0.1
ppm (yellow) shielding, were used to visualize the TSNMRS of
1–8 (cf. Fig. 5, vide infra).
˚
˚
˚
lattice of -10 A to +10 A utilizing a step size of 0.5 A in all
three directions of the Cartesian coordinate system. The zero
points of the coordinate system were positioned at the centers
of the quinoxalyl moiety in 7 and 8 and at the centers of the
carbonyl groups in 3–6. The resulting 68,921 NICS values obtained
Dynamic NMR spectroscopy
1
The H NMR spectra were first recorded at room temperature.
The five-membered ring attached to the rigid TH-DCPD skeleton
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Fig. 1 Correlation of computed d(13C) vs. experimental d(13C) for DCPD derivatives 1a, 2a, 4b,c, 6b,c, 7a and 8a (cf. Scheme 1).
should be highly flexible and, moreover, rapidly interconverting
on the NMR timescale at this temperature. To the best of our
knowledge, this dynamic ring inversion process has not been
studied previously (Scheme 4). Because extremely low barriers to
ring inversion were expected,46 the compounds were dissolved in a
freon mixture (CD2Cl2/CHFCl2/CHF2Cl = 1 : 1 : 3) and variable-
temperature 1H NMR spectra recorded in steps down to 103 K (cf.
Fig. 2 for compound 8a). The proton signals did broaden upon
lowering of the temperature, with the strongest effects observed
for the protons of the five-membered ring. However, none of the
signals were observed to decoalesce into distinct conformer signals.
The same result was also obtained for the remaining endo and the
corresponding exo isomers studied, whereby decoalescence of the
signals was not observed.
Fig. 2 Variable temperature 1H NMR spectra of compound 8a.
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Fig. 3 Variable temperature 1H chemical shifts of the protons of 8a.
For the endo isomers, the proton signals were observed to shift
upon reduction of the temperature (cf. Fig. 3). The shielding
shift of the two C-2 protons was extraordinary, with chemical
shift differences of ca. -0.3 and -0.9 ppm, respectively, observed
upon going from 298 to 103 K. Feasible interpretations of these
observations include that (i) the five-membered ring inversion
remains fast on the NMR timescale (even at 103 K), and that
(ii) due to K = [syn]/[anti], –DG◦ = RT ln K, the conformational
equilibrium is increasingly shifted to one side (in all probability
to the endo/syn conformer because of the extremely high field
position of the H-2 signals as a result of the ring-current effect of
the aromatic moiety in 8a, vide infra). The change in position
of the proton signals in the exo isomer 7a upon a reduction
in temperature is much smaller, < 0.05 ppm usually, however,
it is to lower field in complete contrast to the endo isomer
protons. Because the exo isomers are elongated molecules with the
exo/anti preferred conformer (vide infra), these small deshielding
observations are consistent with expectations: in the exo DCPD
derivative 7, all protons on the DCPD skeleton lie in-plane with the
quinoxalyl moiety and can thus experience deshielding due to the
ring-current effect (cf. Fig. 5, vide infra). Structural differences,
due to syn/anti conformers, are far away from the aromatic
moiety. Thus, in agreement with the experiment, only negligible
low temperature chemical shift gradients could be expected
and from the low temperature shifts of the exo diastereomers,
conclusions similar to the conformational equilibrium of the endo
diastereomers cannot be drawn.
Computation of the proton chemical shift differences of the
C-2 protons in 8a (syn/anti conformers) yielded Dn in excess of
1900 and 500 Hz. With the lowest temperature obtained with
our equipment 103 K for Tc, both rate constants kc of 4221 and
1111, respectively, and a barrier to ring inversion below 4.1–4.4
kcal mol-1 for DGπ, can be suggested. Hence, the experimentally
observed extreme broadening of the C-2 protons at 103 K
corroborates the anticipated low barrier to ring inversion.
The dynamic process was also examined by the theoretical
treatment yielding two interesting results (cf. Table 3): For the
endo configurations 2a, 4a, 6a and 8a, the syn conformers are
at least 1.61 kcal mol-1 more stable than their corresponding anti
analogues (in the exo isomers 1a, 3a, 5a and 7a, the anti conformers
Table 3 Computation of the five-membered ring inversion of DCPD derivatives 1a–8a; energies E [kcal mol-1]
Ground states
exo/anti or endo/syn
(preferred conformers)
exo/syn or endo/anti
Compound
Transition state
Barrier to five-membered ring inversion
1a
2a
3a
4a
5a
6a
7a
8a
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
2.14
1.61
2.08
1.62
2.06
1.98
1.98
2.29
4.59
5.21
4.66
5.02
4.81
5.48
4.53
5.29
4.59 (2.45)
5.21 (3.60)
4.66 (2.58)
5.02 (3.40)
4.81 (2.75)
5.48 (3.50)
4.53 (2.56)
5.29 (3.00)
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are, as expected, more stable by at least 1.98 kcal mol-1, cf. Table 3)
and the barrier to ring inversion is low as expected (2.45–5.48
kcal mol-1) from experimental examination of DGπ.
are presented. Three protons in each isomer are highlighted to
emphasize characteristic differences: Whilst H-4,5(endo) in 8a are
deshielded compared with H-4,5(exo) in 7a, one of the H-1,3
protons and one H-2 proton are strongly shielded whilst the others
are only moderately shielded in the comparison of exo 7a and endo
8a. In Fig. 5, the calculated structures of the four conformers of 7a
and 8a, exo/syn, exo/anti, endo/anti and endo/syn, are presented.
For the various conformers, the TSNMRS of the quinoxalyl moity
are visualized as ICSS of various magnitude and sign [-0.1 ppm
(red) deshielding and 5 ppm (blue), 2 ppm (cyan), 1 ppm (green-
blue), 0.5 ppm (green) and 0.1 ppm (yellow) shielding]. Careful
examination of the depictions in Fig. 5 corroborates well the
conclusions of the previous sections with the following points
noted.
To summarize the results thus far, the five-membered ring
inversion dynamic process remains fast on the NMR timescale
even at 103 K—though very near to coalescence—and the syn
conformers in the endo isomers are, surprisingly, the preferred
conformers. Low-temperature shifts of the protons in the exo/endo
diastereomers were observed which are different in both directions
(shielding in endo and deshielding in exo, respectively) and
size (strongest low-temperature shifts for H-2 protons in endo)
which, due to K = [syn]/[anti] and –DG◦ = RT ln K, point to
further increasing population of the endo/syn conformer. Similar
conclusions concerning the syn/anti conformational equilibrium
of the exo diastereomers, due to only negligible low temperature
chemical shift gradients, cannot be drawn. Thus, full experimental
proof for the preferred conformers of the exo/endo isomers has
not been obtained.
(i) Firstly, the protons H-4,5, which are endo in 7 and exo in 8 and
which are not very dependent on the five-membered ring inversion,
can be employed as comparative references. In the exo isomer,
H-4,5 are positioned below the 0.1 ppm shielding ICSS and
proximate to the 0.5 ppm ICSS [precisely, Dd = 0.16 ppm (syn)
and 0.21 ppm (anti)] whilst in the endo isomer, the same protons
are found inside the red (-0.1 ppm) deshielding ICSS (precisely,
Dd = -0.34 ppm). The sufficiently good agreement of Dd = 0.50
ppm and 0.55 ppm, respectively, and the correct sign (shielded
in 7a and deshielded in 8a) with respect to the experimental
observation (Dd = 0.91 ppm) is most promising. It should be
not forgotten that the anisotropic effect of the aryl moiety is
Spatial magnetic properties of quinoxalyl and carbonyl moieties
for the preferred DCPD conformers
For the aforementioned reason, the spatial magnetic properties
(i.e. TSNMRS) of the carbonyl groups in 3–6 and of the quinoxalyl
moiety in 7 and 8 were calculated and 1H chemical shift differences,
1
Dd, in the H NMR spectra relative to the reference compounds
1
only one effect influencing the H chemical shift as there is also
1 and 2 evaluated (cf. Table 1). The procedure and conclusions
are described for the quinoxalyl derivatives 7a and 8a and can be
taken as examples for the other cases.
In Fig. 4, the experimental 1H NMR spectra of the exo
and endo isomers, 7a and 8a, respectively, at room temperature
steric compression which propels the proton chemical shift in the
opposite direction15,16 and which, furthermore, is quite capable of
masking the anisotropic effect altogether.8 With regards to the
other protons of the five-membered ring, the ring-current effect of
Fig. 4 1H NMR spectra of exo 7a and endo isomers 8a.
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Table 4 Experimental 1H chemical shift differences opposed to the ring-
current effect of the aryl moiety in 7a and 8a
a
c
Proton Ddexp exo/antib exo/synb endo/antib DDd endo/synb DDdd
H-4,5 0.84 0.16
H-1,3 -0.55 -0.28
-0.11 -0.14
0.21
-0.34
0.92
0.08
0.14
0.72
0.50 -0.34
0.55
1.20 0.24
1.18
0.22 0.13
0.16
0.24 0.50
0.15
0.50
0.55
0.52
0.50
0.27
0.21
0.60
0.51
2.87
2.74
-0.26
-0.08
-0.01
-0.12
H-2
-0.80 -0.1
-1.93 -0.25
0.97 2.62
0.84
a Experimental chemical shift differences of the corresponding protons
between 7a and 8a. b Ring-current effect (cf. Fig. 5) of the quinoxalyl
moiety in the four conformers (cf. Scheme 4) of 7a and 8a. c Chemical shift
differences of the ring-current effect of the quinoxalyl moiety between the
conformers endo/anti and exo/anti and exo/syn, respectively. d Chemical
shift differences of the ring-current effect of the quinoxalyl moiety between
the conformers endo/syn and exo/anti and exo/syn, respectively.
value of only 0.48 ppm could be conceivable, but together with
point (iv) this is less probable.
(iv) Protons H-2 in the endo isomers are the most strongly
influenced by the ring-current effect of the aryl moiety and readily
clarify the conformational state. In the syn conformation, the H-
2(syn) proton is positioned below the 2 ppm ICSS (precisely, Dd =
2.62 ppm) and the corresponding H-2(anti) proton exactly at the
0.5 ppm ICSS (precisely, Dd = 0.50 ppm). Less notable effects
are observed in the corresponding anti conformer where the H-
2(syn) proton is positioned between the 0.5 ppm shielding ICSS
and the 1 ppm shielding ICSS (precisely, Dd = 0.715 ppm) and H-
2(anti) is below the 0.1 ppm shielding ICSS (precisely, Dd = 0.14
ppm). Compared with the experimental chemical shift differences
(Dd = 0.76 ppm and 1.98 ppm, respectively), the direction of the
proton chemical shifts changes are in agreement (the endo isomer
compared with the exo isomer is shielded) and similarly for the
Dd values as well. The ring-current effect on H-2(syn), due to
extreme steric compression, is overestimated (Dd = 2.87 ppm)
and the difference to the experimental value of Dd = 1.91 ppm
originates from steric hindrance for this proton.15,16
Fig. 5 Structures of syn/anti conformers of exo/endo isomers 7a and 8a
together with the ring-current effect of the quinoxalyl moiety visualized as
ICSS of various size and direction [-0.1 ppm (red) deshielding and 5 ppm
(blue), 2 ppm (cyan), 1 ppm (green-blue), 0.5 ppm (green) and 0.1 ppm
(yellow) shielding].
thequinoxalyl moietyis decisivelydependenton boththe exo/endo
configuration and the syn/anti conformation of the attached five-
membered ring.
(ii) For the exo configuration, both the H-1,3 and H-2 protons
are well away from any shielding influences. Actually, in the two
syn/anti conformations they are positioned inside the -0.1 ppm
deshielding ICSS (precisely, Dd = -0.28 ppm or up to -0.01 ppm
only), or even outside of it with even smaller influence of the
ring-current effect of the aryl moiety on the corresponding proton
chemical shifts. Hence, the ring-current effect of the attached aryl
moiety does not provide any influential effects concerning the
preferred conformer of the exo isomer and it remains that the
exo/anti conformer has the higher computed stability compared
to its exo/syn analogue (vide supra).
1
All experimental and computed H chemical shift differences
are given in Table 4; Ddexp and Ddcalc. for the endo(syn) conformer
compared with the endo(anti) conformer are highlighted and
strikingly corroborate this structure as the preferred conformer
of the DCPD derivative 8a.
(iii) A different situation exists for the endo isomers. In the anti
conformation, the H-1,3(syn) protons are positioned below the 1
ppm shielding ICSS whilst the corresponding H-1,3(anti) protons
are outside the 0.1 ppm ICSS (precisely, Dd = 0.92 ppm and 0.08
ppm, respectively). The same H-1,3 protons in the corresponding
syn conformation are found below the 0.1 ppm shielding ICSS
(precisely, Dd = 0.24 ppm and 0.13 ppm, respectively). Compared
with the experimental chemical shift differences (Dd = 0.48 ppm
and 0.07 ppm, respectively), the direction of the chemical shift
changes is correct (the two H-1,3 signals are shielded in the endo
isomers compared with the exo isomers), but the magnitude of
the shifts indicates a preference for the endo/syn conformer. As
As another proof for the preferred exo/anti conformer of 7a and
the endo/syn conformer of 8a, the H,H-coupling constants of these
conformers and also of the corresponding exo/syn and endo/anti
conformers (the comparison of experimental and calculated
coupling constants were successfully employed in conformational
analysis),47 were computed at the same level of theory: the values
are given in Table 5 together with the experimental coupling
constants which were obtained by PERCH simulation48 of the 1H
NMR spectra of 7a and 8a, respectively. The agreement between
simulated and experimental spectra (cf. Fig. 6 and 7) prove to
be excellent, hence, realistic coupling constants were obtained in
contrast to present signal overlap, many long range H,H coupling
constants and second order effects. If the experimental coupling
constants are compared with the theoretical values as calculated
1
already mentioned, the second effect on the H chemical shift is
steric compression and increased steric hindrance deshields the
corresponding proton so that the computed shieldings of one H-
1,3 proton by more than 1 ppm compared with the experimental
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Table 5 Experimental H,H-coupling constants of both exo isomer 7a and
the endo isomer 8a, together with the corresponding values as calculated for
the corresponding conformers exo/syn, exo/anti, endo/syn and endo/anti,
respectively
Table 6 Anisotropic effects (as TSNMRS) of carbonyl group(s) on five-
membered ring protons in 3–6
Com-
pound Protons Dd(exo/anti) Dd(exo/syn) Dd(endo/anti) Dd(endo/syn)
3JH,H coupling constants (Hz)
3/4 H-4/5 -0.015 (0.28) —
5/6 H-4/5 0.21
-0.13 (-0.03) -0.125
Calc.
—
-0.16
-0.17
3/4 H-1/3 -0.01 (-0.04) —
0.12 (0.515)
0.1 (0.54)
0.1 (0.04)
0.18 (0.065)
0.1 (0.275)
0.1 (0.29)
0.14 (0.42)
0.26 (0.78)
Proton
Exp.
exo/syn
exo/anti
5/6 H-1/3 -0.04 (-0.13) —
3/4 H-2
5/6 H-2
-0.02 (0.0)
—
6,5
6,4
6,8
0.43
-0.71
0.07
0.64
-0.70
0.73
0.63
-0.65
0.51
-0.04 (-0.02) —
6,7syn
6,7anti
6,1anti
6,1syn
1.49
1.45
-0.16
0.19
1.27
1.51
-0.33
0.13
1.42
1.35
-0.13
-0.03
8.13
which, on the other hand, confirms that now-a-days computa-
tional possibilities provide coupling constants with “analytical
precision”.
5,4
8.76
6.78
The same conformational analysis of the endo isomer 8a is
less clear. For sure, there is better agreement between experiment
and calculation in case of endo/syn, however, for 3J[5,1(syn)]
and 3J[1(syn),2(anti)] major differences were observed (endo/syn:
calculated 0.56 Hz and 0.38 Hz, respectively, but experimental
values are 3.50 Hz and 4.22 Hz, respectively) which point to an
existing conformational equilibrium with two adequately popu-
lated conformers. Boltzmann weighting [employing as boarder
case in addition to the values of endo/syn (vide supra) the
corresponding endo/anti coupling constants which are 8.28 Hz
and 11.52 Hz, respectively] delivered coincident results: 62% to
66% endo/syn and 34% to 38% endo/anti. With this result in hand,
5,7syn
5,1anti
5,7anti
5,2anti
5,1syn
5,2syn
7syn, 7anti
1anti, 4
1anti, 3anti
1anti, 2anti
1anti, 1syn
1anti, 2syn
2anti, 1syn
2anti, 2syn
1syn, 4
1syn, 3anti
1syn, 3syn
1syn, 2syn
6,5
6,4
6,8
6,7syn
6,7anti
6,1syn
6,1anti
5,4
5,7syn
1.51
8.33
0.89
9.40
0.83
7.64
-0.37
-0.29
8.82
-0.73
-10.52
-0.15
1.90
6.70
-12.53
1.22
12.75
-12.27
-0.53
-0.34
0.37
6.52
4.88
0.26
1.61
1.38
1.65
-0.51
-0.04
0.68
-0.78
-9.20
-0.19
-0.15
8.02
-12.30
10.90
0.35
-11.80
-0.87
-0.81
0.59
7.41
4.78
-0.10
0.73
1.48
1.27
-0.10
-0.49
8.35
-0.50
-0.06
8.00
-0.84
-9.15
-0.16
1.14
5.67
-11.20
0.42
11.40
-10.70
-0.64
-0.56
0.07
5.39
4.52
-0.07
0.52
1.56
1.22
1
it is clear why simulated H NMR spectra on basis of calculated
coupling constants of both conformers endo/syn and endo/anti,
respectively, did not agree with the experimental proton NMR
spectrum of 8a and why the protons in 8a are high field shifted
when lowering the temperature. The population of endo/syn, the
more stable conformer, increases with lowering the temperature on
behalf of endo/anti in complete agreement with the conclusions
drawn from the spatial magnetic properties of these structures.
0.08
-0.27
-0.11
10.52
-0.40
8.28
-0.15
10.06
-0.03
3.50
-0.40
0.56
0.23
Anisotropic effect of carbonyl group(s) on the 1H NMR spectra of
DCPD derivatives
5,1syn
5,7anti
0.38
0.24
5,2syn
5,1anti
5,2anti
7syn, 7anti
1syn, 4
1syn, 3syn
1syn, 2syn
1syn, 1anti
1syn, 2anti
2syn, 1anti
2syn, 2anti
1anti, 4
1anti, 3syn
1anti, 3anti
1anti, 2anti
-0.33
-0.84
-0.80
The same methodology can now be applied to study the
anisotropic effect of one (for 3 and 4) and two carbonyl groups
(for 5 and 6) on the 1H NMR spectra of these compounds
relative to compounds 1 and 2. As for the aryl moiety in 7
and 8, the ring protons H-1 to H-5, which are dependent on
the exo/endo configuration and the syn/anti conformation, can
be duly considered (the corresponding Dd TSNMRS data of the
9.38
8.71
7.63
0.30
0.07
-0.04
-8.33
-0.61
0.12
-9.63
-0.59
0.71
7.30
-13.52
4.22
-8.28
-0.77
0.58
7.31
-11.94
0.38
10.71
-12.39
-0.25
-0.75
-0.12
7.74
5.51
-11.62
11.52
0.43
-10.73
-0.31
-0.57
0.79
9.32
1
anisotropic effects on the corresponding H chemical shifts are
given in Table 6).
-13.06
-0.29
-0.46
0.18
In the exo isomers (for both syn and anti conformations), these
protons are too distant from the carbonyl moieties and do not
experience anisotropic effects and thus were not, except for H-4,5,
considered. Although anisotropic effects on the latter protons are
small (maximum 0.21 ppm), the direction of the shift is, however,
reversed in the exo/endo isomers, where remarkable chemical shift
differences of up to Dd = 0.4 ppm could be generated.
The anisotropic effects of the carbonyl groups on the proton
chemical shifts are more intense in the endo isomers for both syn
and anti conformations. The protons syn to the carbonyls of the
H-1,3 methylene groups in the anti conformation and the proton
syn to the carbonyls of the H-2 methylene group are strongly
7.74
5.79
for the various conformers, the agreement between experiment
and exo/anti and disagreement with exo/syn completely confirms
in case of 7a our aforementioned results—exo/anti proves to be
the anancomeric stereoisomer of 7a. This is clearly corroborated
if the two theoretical spectra, on basis of computed H,H cou-
pling constants, are compared with the experimental H NMR
spectrum of this compound (cf. Fig. 8); only in the case of
exo/anti is there agreement, actually already complete agreement,
1
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Fig. 6 Experimental and PERCH-simulated48 1H NMR spectrum of the exo diastereomer 7a.
Fig. 7 Experimental and PERCH-simulated48 1H NMR spectrum of the endo diastereomer 8a.
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Fig. 8 Computed 1H NMR spectra of exo/syn (green) and exo/anti conformers (blue) of 7a in comparison with the corresponding experimental (red)
proton NMR spectrum of this compound.
shielded (Dd = 0.54 ppm and up to 0.78 ppm, respectively), the
corresponding protons anti to the carbonyls are shielded as well
but only to a minor degree (Dd = 0.1 ppm and up to 0.29 ppm,
respectively). The same is also true for the syn H-2 proton. In the
case of the monocarbonyl compound, Dd = 0.42 and 0.78 ppm
in comparison to the corresponding endo dicarbonyl compound
6. Thus, although remarkable carbonyl anisotropic effects on the
1H NMR spectra of 4 and 6 can be expected, it is not possible
to compare the values obtained with the experimental chemical
shift differences because only the 7-chloro/7-bromo derivatives
(cf. Scheme 1) and not the parent compounds are experimentally
available. Only the proton chemical shift of one of the H-2 protons
in 6b,c at 1.17 ppm may be employed as experimental proof of
the strong shielding of the corresponding syn proton, subject to
the carbonyl group anisotropic effects and for the existence of
the preferred syn conformer in the endo configuration of these
compounds as computed.
calculations. This dynamic process remains fast on the NMR
timescale at 103 K and thus the conformational equilibria could
not be frozen out. Computations provided ring-inversion barriers
of 3.0–5.48 kcal mol-1 and strongly one-sided conformational
equilibria (DG◦ > 1.6 kcal mol-1) for the anti conformer of the
exo isomers and, surprisingly, for the syn conformer of the endo
isomers. TSNMRS as spatial magnetic properties (spatial NICS)
of attached aryl (quinoxalyl) and carbonyl functional groups were
successfully employed to prove the two conformations as the pre-
ferred conformers by agreement with the experimental chemical
shift differences. This result was impressively corroborated by em-
ploying computed H,H-coupling constants for the same purpose.
Because of persistent strong reservations to qualify molecular
response properties such as experimentally proven anisotropic
effects of functional or aromatic groups on the 1H chemical
shifts of proximate protons by unobservable quantities like
NICS,24a the results of this study can serve as definitive proof
of TSNMRS (spatial NICS) to not only successfully assign the
configuration and diastereoisomerism of structures,2–14 but also
the conformational state if the underlying dynamic process is fast
on the NMR timescale. TSNMRS help visualize and quantify the
anisotropic effects of functional groups in NMR spectra which can
be measured experimentally and which can serve as the molecular
response property of spatial NICS.
Conclusions
The conformational state, with respect to the five-membered ring
inversion for the exo and endo configurations of the tetrahy-
drodicyclopentadiene derivatives 1–8, was studied by variable-
temperature dynamic NMR spectroscopy and by theoretical
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at 50 ◦C. After removing the methanol, the residue was dissolved
in diethyl ether, washed with water and dried with Na2SO4. The
ether was removed under reduced pressure, yielding crystals, which
were recrystallized from n-hexane. The product was obtained as
Experimental Section
All melting points were determined on a Boetius micro hostage
microscope (Fa. Analytik Dresden). The IR spectra (KBr) were
recorded with a Perkin Elmer FT-IR 1600 spectrometer (n/cm-1).
The mass spectra were recorded on a Finnigan-MAT SSQ 710
(70 eV). ESI-MS spectra were obtained in positive ion mode using
a Q-TOFmicro mass spectrometer (Micromass Manchester, UK)
which was equipped with an ESI source; analytes were injected
using the syringe pump (Harvard Apparatur Ltd., Edenbridge,
UK) at a flowing rate varying from 2 to 20 mL min-1 and the
capillary voltage was set to 2.6 kV. Elemental compositions were
determined by accurate measurements with deviations less than
10 ppm from the calculated values. Elemental analyses were
performed on an autoanalyzer CHNS-932 (Fa. Leco instruments
GmbH); reliable micromasses were obtained for all substances
◦
colorless needles in 93% yield. Mp. 39–41 C; IR (KBr, cm-1):
1
735 (C–Cl), 1060 (C–O), IR(CCl): 3586 (OH); H NMR (ppm,
CDCl3): 4.08 (tr, 1H, J = 1.30 Hz), 3.96 (ddd, 1H, J = 1.52, 3.61,
7.74 Hz), 2.46–2.38 (m, 3H), 2.29 (m, 1H), 2.26 (ddd, 2H, J =
1.14, 7.74, 14.42 Hz), 1.88 (ddtr, 1H, J = 1.51, 4.13, 14.42 Hz),
1.63 (m, 2H), 1.52 (m, 4H); 13C NMR (ppm, CDCl3): 70.77 (1C,
C–OH), 66.45 (1C, C–Cl), 54.06 (1C, CH), 47.84 (1C, CH), 41.50
(1C, CH), 40.80 (1C, CH), 34.87 (1C, CH2), 27.97 (1C, CH2), 27.44
(1C, CH2), 26.79 (1C, CH2); Anal. Calcd for C10H15ClO: C: 64.34,
H: 8.10, found: C: 64.54, H: 7.61.
General procedure I – Oxidation of halogenohydrines to
halogenoketones
1
(C, H 0.3%). H and 13C NMR spectra were recorded on a
Bruker Avance 500 or 300 MHz spectrometers using 5 mm probes
operating at 500 and 300 MHz for H, respectively, and 125 and
1
To a stirred mixture of the adequate alcohol (0.25 mol) and
diethylether (125 mL), 250 mL of a solution of Na2Cr2O7 · 2H2O
(0.17 mol, 50 g) and H2SO4 (0.67 mol) in 250 mL water was added
dropwise at 0 ◦C. The organic phase was separated, washed with
NaOH (0.1 N) and water and dried with Na2SO4. The ether was
removed by a rotary evaporator and the residue distilled under
reduced pressure.
75 MHz for 13C, respectively, and the low temperature NMR
spectra on a Bruker AV 600 (at 600 and 150 MHz, respectively).
Chemical shifts were determined relative to residual CHCl3 (1H, d
7.27), internal CDCl3 (13C, d 77.0), internal CD2Cl2 (13C, d 53.73)
and are given in ppm downfield to TMS (for 1H, 13C). Analysis and
assignment of the 1H NMR data were supported by homonuclear
(COSY) and heteronuclear (HSQC 13C-1H, HMBC 13C-1H) 2D
correlation experiments. A solvent mixture of CD2Cl2, CHFCl2,
and CHF2Cl in a ratio of 1 : 1 : 3 was used for the low temperature
measurements. The probe temperature was calibrated by means
of a thermocouple PT 100 inserted into a dummy tube. The low
temperature measurements were estimated to be accurate to 2 K.
The chemical shifts difference Dnc, Hz was computed at B3LYP/6-
31G(d,p) level of theory and used to calculate kc and the ring
inversion barriers by the Eyring equation at Tc.
7-syn-chloro-tetrahydro-endo-DCDP-9-one (4b)
This compound was synthesized from 7-syn-chloro,9-exo-
hydroxy-tetrahydro-endo-DCDP following the general procedure
I. 7-Syn-chloro-tetrahydro-endo-DCDP-9-one was obtained as
colourless oil in 76% yield.
Bp1.5: 110–112 ◦C; nD20: 1,5278; IR (KBr, cm-1): 745 (C–Cl), 1749
(C O); Anal. Calcd for C10H13OCl: C: 65.04, H: 7.10, found: C:
65.00, H: 7.082; 1H NMR (ppm, CDCl3): 4.28 (ddd 1H), 2.72 (m,
1
Preparation of 7-syn-chloro,9-exo-acetoxy-tetrahydro-endo-
DCDP
4H), 2.58 (dd, H, J = 18.53, 4.98 Hz), 2.16 (dd, 1H, J = 18.48,
2.58 Hz), 1.62 (m, 5H), 1.39 (m, 1H); MS (m/e, relative intensity):
185 [M35Cl + 1]+, 2), 120 (C9H12+, 100), 107 (C8H9 , 44), 79 (C6H5 ,
78).
+
+
To a stirred solution of 1,2-dihydro-exo-DCDP (0.50 mol, 67.1 g)
in acetic acid (400 mL) t-butyl hypochlorite (0.50 mol, 54.3 g) was
added dropwise at 20 ◦C. After removing the acetic acid under
vacuum conditions, the residue was treated with diethyl ether,
washed with NaOH (0.1 N) and water and dried with Na2SO4.
The ether was removed by rotary evaporation and the residue was
distilled under vacuum conditio◦ns, leaving colorless oil in 63%
yield. nD22: 1.5068; Bp: 118–120 C: IR (KBr, cm-1): 726 (C–Cl),
7-syn-bromo-tetrahydro-endo-DCDP-9-one (4c)
This compound was synthesized from 7-syn-bromo,9-exo-
hydroxy-tetrahydro-endo-DCDP following the general procedure
I. 7-Syn-bromo-tetrahydro-endo-DCDP-9-one was obtained as
colorless oil in 84% yield.
1
1735 (C O); H NMR (ppm, CDCl3): 4.89 (ddd, 1H, J = 1.30,
Bp1.5: 132–133 ◦C; nD20: 1.5510; IR (KBr, cm-1): 722 (C–Br),
1760 (C O); MS: m/e (relative intensity): 229 (M79Br + 1)+, 14),
3.93, 7.60 Hz), 4.01 (tr, 1H, J = 1.1 Hz), 2.53–2.29 (m, 4H), 2.19
(ddd, 1H, J = 1.33, 7.64, 14.24 Hz), 2.09 (d, 1H, J = 2.66 Hz),
2.03 (s, 3H), 1.68–1.46 (m, 6H); 13C NMR (ppm, CDCl3): 171.00
(1C, C O), 72.31 (1C, C–OR), 64.75 (1C, C–Cl), 51.92 (1C, CH),
47.74 (1C, CH), 41.81 (1C, CH), 41.32 (1C, CH), 31.14 (1C, CH2),
28.20 (1C, CH2), 27.31 (1C, CH2), 26.64 (1C, CH2), 21.34 (1C,
CH3); Anal. Calcd for C12H17ClO2: C: 63.02, H: 7.49, found: C:
61.63, H: 7.06.
149 (C10H13O+, 26), 107 (C8H11+, 100), 79 (C6H7 , 92); H NMR
(ppm, CDCl3): 4.28 (m, 1H), 2.78–2.68, m, 4H), 2.61 (dd, 1H, J =
18.53, 4.53 Hz), 2.16 (dd, 1H, J = 18.53, 2.88 Hz), 1.79–1.70 (m,
1H), 1.70–1.50 (m, 4H), 1.39 (m, 1H); Anal. Calcd for C10H13OBr:
C: 52.42, H: 5.72, found: C: 52.32, H: 5.791.
+
1
General procedure II – Oxidation of 7-syn-halogeno-
tetrahydro-endo-DCPD-9-ones to 7-syn-halogeno-
tetrahydro-endo-9,10-diones
Preparation of 7-syn-chloro,9-exo-hydroxy-tetrahydro-endo-
DCDP
7-syn- chloro,9-exo-acetoxy-tetrahydro-endo-DCDP (0.10 mol,
A
mixture of 7-syn-halogeno-tetrahydro-endo-DCDP-one
22.8 g) was treated with KOH (0.10 mol, 5.6 g) in 100 mL methanol
(0.07 mol), selenedioxide (0.2 mol, 22.2 g) and 5 drops of water
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in nitrobenzene (120 mL) was stirred for 5 h at 140 ◦C. Ether
was then added, selen was removed by filtration and the solution
was washed with NaOH (0.1 N) and water. After drying, both
solvents were removed on a rotary evaporator. The residue was
treated with ether and then purified by chromatography (Al2O3
neutral; pentane/ether, 1 : 5). The yellow residue obtained was
recrystallized from acetone/hexane, 1 : 5.
1580 (C C valence), 1510 (C N valence), 1460 (CH2 deform),
1363 (C–N valence).
Acknowledgements
Dr Karel D. Klika is thanked for language correction of the
manuscript.
7-syn-chloro-tetrahydro-endo-DCDP-9,10-dione (6b)
Notes and references
This compound was synthesized from 7-syn-chloro-tetrahydro-
endo-DCDP-one 4b following the general procedure II. 7-syn-
chloro-tetrahydro-endo-DCDP-9,10-dione 6◦b was obtained as
yellow crystals in 61% yield. Mp: 109–110 C; IR (KBr, cm-1):
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11 E. Kleinpeter, A. Schulenburg, I. Zug and H. Hartmann, J. Org. Chem.,
2005, 70, 6592.
1
752 (C–Cl), 1755–1776 (C O); H NMR (600 MHz, CDCl3):
4.55 (tr, 1H, J = 3.90 Hz), 3.29 (m, 2H), 3.02 (m, 2H), 1.68 (m,
2H), 1.63 (m, 1H), 1.46 (m, 2H), 1.17 (m, 1H); MS m/e (relative
intensity): 198 (M35Cl+, 53), 237 (M37Cl+, 12), 107 (C11H8 , 100);
Anal. Calcd for C10H11O2Cl: C:60.46; H:5.58, found: C: 60.59; H:
5.51.
+
7-syn-bromo-tetrahydro-endo-DCDP-9,10-dione (6c)
This compound was synthesized from 7-syn-bromo-tetrahydro-
endo-DCDP-one 4c following the general procedure II. 7-Syn-
bromo-tetrahydro-endo-DCDP-9,10-dione 6c was obtained as
12 E. Kleinpeter and A. Schulenburg, J. Org. Chem., 2006, 71, 3869.
13 M. Heydenreich, A. Koch, S. Klod, I. Szatma´ri, F. Fu¨lo¨p and E.
Kleinpeter, Tetrahedron, 2006, 62, 11081.
◦
yellow crystals in 49% yield. Mp: 101 C; IR(KBr, cm-1): 752
(C–Br), 1752–1778 (C O); 1H NMR (600 MHz, CDCl3): 4.39 (tr,
1H, J = 1.85 Hz), 3.34 (m, 2H), 3.02 (m, 2H) 1.7 (m, 2H), 1.64 (m,
1H), 1.47 (m, 2H), 1.18 (m, 1H); MS: m/e (relative intensity): 243
14 E. Kleinpeter, A. Koch, H. S. Sahoo and D. K. Chand, Tetrahedron,
2008, 64, 5044.
15 E. Kleinpeter, A. Koch and P. R. Seidl, J. Phys. Chem. A, 2008, 112,
[M79Br + 1]+, 5), 107 (C8H11+, 100), 79 (C6H7 ,72); Anal. Calcd for
+
4989.
16 E. Kleinpeter, I. Szatma´ri, L. La´za´r, A. Koch, M. Heydenreich and F.
Fu¨lo¨p, Tetrahedron, 2009, 65, 8021.
C10H11O2Br: C: 49.41; H: 4.56, found: C: 49.53; H: 4.53.
17 E. Kleinpeter, S. Klod and A. Koch, THEOCHEM, 2007, 811, 45 and
references therein.
General procedure III – Synthesis of quinoxaline derivatives 7 and
8 from the corresponding diketones 5 and 6, respectively
18 E. Kleinpeter, A. Holzberger and Ph. Wacker, J. Org. Chem., 2008, 73,
56.
19 E. Kleinpeter and A. Koch, J. Phys. Chem. A, 2010, 114, 5928.
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112, 10895.
21 E. Kleinpeter, A. Koch, H. S. Sahoo and D. K. Chand, Tetrahedron,
2008, 64, 5044.
A mixture of tetrahydro-DCDP-9,10-dione (1.6 g, 0.01 mol), o-
phenylendiamine (1.1 g, 0.01 mol) and benzene (50 mL) was stirred
at room temperature. The solution was concentrated; purification
of the residue by column chromatography and recrystallization
from methanol.
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Quinoxaline derivative 7a of tetrahydro-exo-DCDP-9,10-dione 5a
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Anal. Calcd for C16H16N2: C: 81.32; H: 6.82, N: 11.85, found:
C:81.26; H: 6.99; N: 11.87. MS m/e (relative intensity): 236 (M+,
100), 237 (M+1, 11), 168 (C11H8N2, 90); H NMR (600 MHz,
CDCl3): 7.96 (m, 2H); 7.63 (m, 2H); 3.29 (m, 2H); 2.27 (dtr, 2H,
J = 12.4, 8.04 Hz); 2.17 (m, 1H); 2.07 (m, 2H); 1.98 (m, 1H); 1.94
(m, 1H); 1.51 (m, 1H); 1.29 (m, 2H); IR (cm-1): 2860, 2879, 2951
(CH2-valence), 1580 (C C valence), 1510 (C N valence), 1460
(CH2 deform), 1363 (C–N valence).
1
Quinoxaline derivative 8a of tetrahydro-endo-DCDP-9,10-dione 6a
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Anal. Calcd for C16H16N2: C: 81.32; H: 6.82, N: 11.85, found:
C:81.09; H: 6.93; N: 11.83. MS m/e (relative intensity): 236 (M+,
100), 237 [M+1]+, 11), 168 [C11H8N2]+, 90); 1H NMR (600 MHz,
CDCl3): 8.02 (m, 2H); 7.66 (m, 2H); 3.43 (dtr, 2H); 3.11 (m, 2H);
2.17 (m, 1H); 2.12 (m, 1H); 1.52 (m, 2H); 1.18 (m, 1H); 1.14 (m,
1H); -0.42 (m, 1H); IR (cm-1): 2860, 2879, 2951 (CH2-valence),
1110 | Org. Biomol. Chem., 2011, 9, 1098–1111
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