E-2-benzylidenebenzocycloalkanones. Stereostructure and NMR spectroscopic investigation

Article abstract of DOI:10.1016/S0022-2860(98)00805-9

Series of E-2-benzylideneindanones (a), -tetralones (b) and - benzosuberones (c) with OCH₃ (2-4), NO₂ (5-7) and F (8-10) substitutions (ortho, meta and para) on their benzylidene moiety were synthesized by aldol condensation of the a

Full text of DOI:10.1016/S0022-2860(98)00805-9

Journal of Molecular Structure 479 (1999) 13–19
E-2-Benzylidenebenzocycloalkanones. Stereostructure and NMR
spectroscopic investigation
a
b
c
c,
*
´
´
P. Perjesi , T. Nusser , Gy. Tarczay , P. Sohar
a
´
Department of Medical Chemistry, University Medical School, POB 99, H-7601 Pecs, Hungary
bChinoin Pharmaceuticals, POB 110, H-1325 Budapest, Hungary
c
´
¨ ¨
Department of General and Inorganic Chemistry, Lorand Eotvos University, POB 32, H-1518 Budapest, Hungary
Received 24 July 1998; received in revised form 20 October 1998; accepted 20 October 1998
Abstract
Series of E-2-benzylideneindanones (a), -tetralones (b) and -benzosuberones (c) with OCH3 (2–4), NO2 (5–7) and F (8–10)
substitutions (ortho, meta and para) on their benzylidene moiety were synthesized by aldol condensation of the appropriate
aldehydes and benzocyclanones. The stereostructure (configuration and conformation) and the electronic properties (conjuga-
1
tion of the enone moiety with the aromatic rings) of the compounds were studied by IR, H and 13C NMR spectroscopy
including also 2D-HSC, DNOE and DEPT measurements. Ab initio calculations were carried out to corroborate the experi-
mental findings. ᭧ 1999 Elsevier Science B.V. All rights reserved.
Keywords: E-2-benzylideneindanones -tetralones -benzosuberones; Stereostructure; IR, H and C NMR spectra; Ab initio geometry optimisation
1. Introduction
have been found to be affected by both the ring size
and the substitution pattern of the benzylidene moiety
[5–7].
Numerous synthetic and natural a,b-unsaturated
carbonyls exhibit remarkable biological activity [1].
Among others, several chalcones and related benzyli-
dene ketones have been reported to possess antifungal
[2], antibacterial [3] and cytotoxic (antitumor) [4]
activities.
Recently we have stated antifungal [5,6] and cyto-
toxic (antitumor) [7] activities of some E-2-benzyli-
deneindanones (a), -tetralones (b), and
The biological activity of the a,b-unsaturated
carbonyl (enone) compounds is considered to be asso-
ciated with their reactivity with the thiol moiety of the
critical peptides and/or proteins [1]. Is this mechanism
true, then electronic and steric factors should affect
the reactivity, i.e. their biological activity. In order to
support this assumption, we have performed a
1
-
comparative IR, H NMR, and 13C NMR study on
benzosuberones (c, see Scheme 1). A number of the
investigated derivatives were found to be more active
than the reference compounds used in the different in
vitro test systems. The observed biological activities
compounds 1a-c–10a-c (Scheme 1).
The aim of this study was to investigate the stereo-
structure (configuration and conformation) and the
electronic properties (conjugation of the enone moiety
with the conjugated and the condensed benzene rings)
of our compounds, which determine their reactivity
with nucleophilic reagents [8].
* Corresponding author (Spectroscopy). Tel.: ϩ 36-1-209-0599;
Fax: ϩ 36-1-209-0602; E-mail: sohar@para.chem.elte.hu
0022-2860/99/$ - see front matter ᭧ 1999 Elsevier Science B.V. All rights reserved.
PII: S0022-2860(98)00805-9

´
14
P. Perjesi et al. / Journal of Molecular Structure 479 (1999) 13–19
Scheme 1.
2. Materials and methods
3. Structure
1
The E-2-benzylideneketones 1–10 were prepared
according to the methods described in the literature
[9,10]. Elemental analysis data (C, H) of the
previously unpublished compounds were within
0.4% of the calculated values. The melting points
(ЊC) and (yields (%)) of unreported compounds are
as follows. 2a: 131–133 (81), 8a: 134–136 (73), 9a:
127–129 (88), 2b: 108–110 (83), 8b: 56–58 (72), 9b:
89–91 (89), 2c: 85–87 (78), 5c: 130–132 (69), 6c:
113–15 (85), 7c: 172–174 (93), 8c: 59–61 (71) and
9c: 75–77 (88).
IR spectra were taken in KBr discs with a
Bruker IFS-55 instrument, controlled by opus 2.0
software. The 1H and 13C NMR spectra were
recorded in CDCl3 solution in 5 mm tubes at
room temperature, on a Bruker DRX-500 spectro-
meter at 500.13 (1H) and 125.76 (13C) MHz, with
the deuterium signal of the solvent as the lock and
TMS as internal standard. The standard Bruker
microprogram noemult.au to generate NOE
[11,12] was used. DEPT spectra [13] were run
in a standard manner [14], using only the Q ˆ
135Њ pulse to separate CH/CH3 and CH2 lines
phased ‘up’ and ‘down’, respectively. The 2D-
HSC spectra [15] were obtained by using the stan-
dard Bruker pulse program hxco.au.
The IR, H and 13C NMR data (Tables 1 and 2)
proved the expected structures of the compounds
investigated, hence, only their stereostructures and
the feature of conjugation in them will be briefly
discussed here.
Theoretically, E and Z geometric isomers can be
equally formed in the reaction used for synthesis of
our compounds. The Z configuration, however, is
highly unfavourable because of strong steric interac-
tion between the aryl and carbonyl groups. Neverthe-
less, for one member of the three series a, b and c
(3a,c and 4b) the E configuration was proved by
DNOE experiments directly. The steric close arrange-
ment of H-20,60 atoms of the aryl group and the
methylene hydrogens vicinal to the Ca (C-2) atom
were confirmed by significant NOE: by saturating
the signal of one of the interacting groups, intensity
enhancement was observed on the signal of the other
group (Table 3).
The carbonyl IR-frequency of the compounds
investigated is decisively determined by the ring
size. The ring strain reveals in higher frequencies
[18] for series a, relative to series b and c by 35 and
34 cmϪ1 (mean values), respectively (Table 4).
The mean value of the nCyO frequencies in the
series a–c are 1698, 1663 and 1664 cmϪ1. Expansion
of electron delocalization including also the aryl
group in the side chain causes lowering in the
nCyO frequency for the meta- and para-substituted
derivatives as compared to the ortho-analogues in
series a to an increasing extent (by 5, 11 and
13 cmϪ1, respectively) in order of substituents F,
NO2 and OMe.
The ab initio geometry optimisation was
carried out using the gaussian 94 [16] program
package at RHF level. The Dunning–Huzinaga
full double zeta basis set was used [17] with
polarisation functions for all atoms. The criteria
of convergence were the standard values of
gaussian 94.

´
P. Perjesi et al. / Journal of Molecular Structure 479 (1999) 13–19
15
g
n
n
n

´
P. Perjesi et al. / Journal of Molecular Structure 479 (1999) 13–19
16
d

´
P. Perjesi et al. / Journal of Molecular Structure 479 (1999) 13–19
17
Table 3
influence of changes in ring size or the position of
the substituent (and simultaneously in equilibriums
Results of DNOE measurements on compounds 3a,c and 4b
of rotamers corresponding to rotations around the
Saturated signal Responses
subset
Cb –CϪAr1 or C
–N(O2) bonds) on the nCyO
H-20 H-60 H-20,60 H-6 yCb H
a
3-CH2
Ar
frequency operates in different proportions; the differ-
ence in frequencies between positional isomers 5a and
6a/7a (5-ring series) is high (11 cmϪ1), while it is
small for benzosuberones (c series), thus the spread
of conjugation changes significantly in the case of a-
type compounds, while only scarcely in series c.
In series b (in the tetralones), both rotational equi-
librium differ for the individual compounds influen-
cing equally the nCyO frequency.
b,c
3-CH2
H-20
3a,c 3a,c
3a
3c
3c
3a,c
3a,c
4b
d
H-60
H-20,60
yCb H
5-CH2
4b
e
3a,c 3a,c 4b
b
a Vicinal to yC(a). Further responses:
b,c 4-CH2 (3c, 4b)
d H-50 (3a,c)
e H-30,50 (4b).
Very large differences were observed in the 1H
NMR spectra of ortho- and meta/para-substituted
compounds for the chemical shifts Hb in series a,
the mean downfield shift is 0.56, 0.26 and 0.28 ppm
in the cases of OMe, NO2 and F substituents. In the b
and c series much smaller and scarcely different from
one another shift differences (0.09–0.22 ppm) were
measured. The delocalization in the enone system
and consequently the bond polarization, thus causes
the paramagnetic shifts [20] of the Hb signal to be
diminished by the buffering effect of the aryl group
of electron-reservoir nature in coplanar arrangement,
possible for meta- and para-substituted derivatives.
From the above data, in accord with the IR frequen-
cies, it may be concluded, that:
In the fluoro compounds the ring size did not influ-
ence the frequency difference of positional isomers.
The slightly higher nCyO frequency of the ortho-
fluoro compounds is due to the ϪI effect of the substi-
tuents [19] being more effective in this position
instead of a change in the conformational equilibrium
corresponding to the rotation around the Cb –CAϪr1
bond.
The same is valid for the methoxy-analogues in
series b and c (including six- and seven-membered
rings). In series a, however, a spectacular change is
observable in the nCyO frequency, hence in the parti-
cipation of the aryl group in the conjugation; the
conjugation spreads into the aryl group, which reveals
itself in a lowering of the nCyO frequency by 15 and
11 cmϪ1, respectively, for 3a and 4a as compared to
2a.
1. the enone moiety is planar in series a and non-
planar for series b and c.
2. in series a the aryl group is also coplanar with the
enone moiety, thus for this series a fully planar
molecular skeleton is characteristic, while in series
Nitro compounds represent an intermediate case
between the fluoro and methoxy derivatives. The
Table 4
Spectral data on compounds 1a–10a, 1b–10b and 1c–10c relevant to electron distribution (conjugation) and stereostructure (conformational
equilibrium)
Assignment
Spectrum
Position of aryl substituent
Series (x-membered ring)
a (5)
b (6)
c (7)
nCyO
yCH(Ar)
[Hb ]
IR
1698 ^ 8
7.62 ^ 0.07
8.12
1663 ^ 3
7.80 ^ 0.10
8.02
1664 ^ 3
7.76 ^ 0.10
8.12
m, p
o
1H NMR
H-9
7.87 ^ 0.05
8.09 ^ 0.07
7.73 ^ 0.07
CyO
194.1 ^ 0.5
16
21
187.4 ^ 0.3
8
11
197.6 ^ 0.6
2
4
13C NMR
m, p
o
Dd[C(a)-C(b)]

´
P. Perjesi et al. / Journal of Molecular Structure 479 (1999) 13–19
18
Table 5
structure) and even stronger for the ortho-substi-
a
Calculated dihedral angles Q1, Q2 and Q3 in compounds 1a-c
tuted compounds where the buffering effect of the
out-of-plane aryl group cannot be effective (c.f.
Table 4).
Q1
Q2
Q3
1a
1b
1c
0
10.4
0
12.7
0
43.5
40.8
2. the mean shift of carbonyl carbons with only slight
fluctuation is 187.4 ppm in the tetralones (series b).
Due to ring strain [15] this value is higher in series
a (194.1 ^ 0.5 ppm) and a further increase can be
observed for series c, the seven-membered alka-
none ring containing benzosuberones (197.6 ^
0.6 ppm). The latter enhancement in the CyO
shift is due to the moderate bond polarization as
compared to series a and b, which results from its
localization to the CyO bond in the non-planar
enone moiety.
Ϫ 32.0
Ϫ 15.3
a c.f. text.
b and c, the conformers with out-of-plane aryl
group to the enone plane are preferred, except for
compounds 9c and 10c, where the aryl group is
coplanar with the CyC bond of the non-planar
enone group in the dominant conformer.
For the H-9 atom of the condensed benzene ring, in
peri position to the carbonyl group, the following
mean chemical shift values were measured in series
a, b and c: 7.87, 8.09 and 7.73 ppm, respectively
(Table 4). Consequently, the coplanar arrangement
of the carbonyl to the condensed ring in series a did
not change significantly in the tetralones (in series b),
and the anisotropic effect of the carbonyl [21] causes
an even larger downfield shift on the H-9 signal. The
higher paramagnetic shift can be explained by the
backforced polarization of the CyO bond in the non-
planar enone group; the anisotropy of the carbonyl
group becomes stronger due to enhanced bond
order.
Quantum chemical calculations were carried out to
support our suggestions from IR and NMR spectro-
scopic investigations concerning the conformational
behaviours of series a, b and c containing 5-, 6- and
7-membered alkanone rings and different substituents
in different positions on the benzene ring of the aryl
group.
Ab initio geometry optimisation on compounds
1a-c lead to results (Table 5) which are in excellent
agreement with our spectroscopic conclusions. They
support
1. the fully planar structure of type a compounds (the
three dihedral angles relevant to conformations are
equally 0Њ);
2. the moderate and considerable distortion of dihe-
dral angle Q1: C(9)–C(9a)–CyO in series b and c,
respectively;
3. the moderate and commensurable change in dihe-
dral angle Q2: OyC–C(a)yC(b)—deviation of
the enone moiety from coplanar arrangement—in
series b and c; and
After all, these facts refer to an essentially unaltered
C(9)–C(9a)–CyO dihedral angle, which deviated
only slightly from 0Њ also in series b. On the other
hand, from the stronger shielding of H-9 in series c
it may be concluded that this dihedral angle signifi-
cantly changes.
From the 13C NMR shifts further conclusions can
be drawn, supporting the above statements:
1. the chemical shift difference of Ca and Cb atoms
(DdCa Cb ) is characteristic of the polarization in
the enone moiety (the extension of delocalization
[22]): the more polarized is the enone group the
higher is DdCa Cb . The mean value of DdCa Cb
is 16, 8 and 2 ppm in the 5-, 6- and 7-membered
alkanone ring containing series a, b and c for meta-
and para-substituted compounds, while for ortho-
analogues more enhanced data were observed (21,
11 and 4 ppm, respectively). Hence, enone polar-
ization is most pronounced in series a (full planar
4. the similar and significant distortion in dihedral
angle Q3: C(a)yC(b)–C(1,Ar)–C(2,Ar) in both
series b and c: the preference of the non-planar
arrangement of the aryl group and the enone
moiety.
Acknowledgements
´
The authors are indebted to Dr A Csampai and Mrs.
¨
A. Boszin-Nagy for skilled technical assistance.

´
P. Perjesi et al. / Journal of Molecular Structure 479 (1999) 13–19
19
Resolution Multipulse NMR Spectra Editing and DEPT,
Bruker, Karlsruhe, 1982.
[15] R.R. Ernst, G. Bodenhausen, A. Wokaun, Principles of
Nuclear Magnetic Resonance in One and Two Dimension,
Clarendon Press, Oxford, UK, 1987, 471–479.
Thanks are also due to the Hungarian Research Foun-
dation (OTKA) for financial support.
References
[16] gaussian 94 (Revision B.2), M.J. Frisch, G.W. Trucks,
H.B. Schlegel, P.M.W. Gill, B.G. Johnson, M.A. Robb,
J.R. Cheeseman, T.A. Keith, G.A. Petersson, J.A.
Montgomery, K. Raghavachari, M.A. Al-Laham, V.G.
Zakrzewski, J.V. Ortiz, J.B. Foresman, J. Cioslowski,
B.B. Stefanov, A. Nanayakkara, M. Challacombe, C.Y.
Peng, P.Y. Ayala, W. Chen, M.W. Wong, J.L. Andres,
E.S. Replogle, R. Gomperts, R.L. Martin, D.J. Fox, J.S.
Binkley, D.J. Defrees, J. Baker, J.P. Stewart, M. Head-
Gordon, C. Gonzales and J.A. Pople, Gaussian Inc., Pitts-
burgh Pa, 1995.
[1] J.R. Dimmock, M.L.C. Wong, Can. J. Pharm. Sci. 11 (1976)
35–53.
[2] T.M. Al-Nakib, V. Bezjak, M.J. Meegan, R. Chandy, Eur. J.
Med. Chem. 25 (1990) 455–462.
[3] E. Erciyas, H.I. Erkaleli, G. Cosar, J. Pharm. Sci. 83 (1994)
545–548.
[4] R.J. Anto, K. Sukumaran, G. Kuttan, M.N. Rao, V. Subbaraju,
R. Kuttan, Cancer-Lett. 97 (1995) 33–37.
´
[5] T.M. Al-Nakib, P. Perjesi, R. Varghese, M.J. Meegan, Med.
Princip. & Pract. 6 (1997) 14–21.
´
[17] T.H. Dunning Jr., P.J. Hay, in: H.F. Schaefer (Ed.), Modern
Theoretical Chemistry, vol. 3, Plenum, New York, 1976, 1–
28.
[6] P. Perjesi, T.M. Al-Nakib, R. Varghese, Med. Princip. Pract.,
in preparation.
´
[7] P. Perjesi et al., unpublished results.
´
´
[18] S. Holly, P. Sohar, in: L. Lang, W.H. Prichard (Eds.), Theo-
[8] D. Duval, S. Geribaldi, Nucleophilic attacks on enones, in: S.
Patai, Z. Rappoport (Eds.), The Chemistry of Enones, vol. 1,
Wiley, Chichester, 1989, 355–469.
retical and Technical Introduction to the Series ‘‘Absorption
Spectra in the Infrared Region’’, Akademiai Kiado, Budapest,
´
´
1975, 97.
[9] A.T. Nielsen, W.J. Houlihan, The aldol condensation, in:
Organic Reactions, vol. 16, Wiley, New York, 1968, 44–47.
[10] A. Hassner, N.H. Cromwell, J. Amer. Chem. Soc. 80 (1958)
893–900.
´
´
[19] S. Holly, P. Sohar, in: L. Lang, W.H. Prichard (Eds.), Theo-
retical and Technical Introduction to the Series ‘‘Absorption
Spectra in the Infrared Region’’, Akademiai Kiado, Budapest,
´
´
1975, 96.
[11] J.K.M. Sanders, J.D. Mersch, Progr. Nucl. Magn. Reson. 15
(1982) 353 and references cited therein..
´
[20] P. Sohar, Nuclear Magnetic Resonance Spectroscopy, vol. 2,
´
CRC Press, Boca Raton, Florida, 1983, 52.
[12] P. Sohar, Nuclear Magnetic Resonance Spectroscopy, vol. 1,
´
[21] P. Sohar, Nuclear Magnetic Resonance Spectroscopy, CRC
CRC Press, Boca Raton, Florida, 1983, 196–197.
[13] D.T. Pegg, D.M. Doddrell, M.R. Bendall, J. Chem. Phys. 77
(1982) 2745.
Press, Boca Raton, Florida, 1, 1983, 32–33 and 2, 51.
´
[22] P. Sohar, Nuclear Magnetic Resonance Spectroscopy, vol. 2,
CRC Press, Boca Raton, Florida, 1983, 181, 182 and 197.
[14] M.R. Bendall, D.M. Doddrell, D.T. Pegg, W.E. Hull, High