Synthesis of a new 1,2,3,4,5-pentasubstituted cyclohexanol and determining its stereochemistry by NMR spectroscopy and quantum-chemical calculations

Article abstract of DOI:10.1002/mrc.4377

The presence of substituents in cyclohexane can influence to the ratio of conformers; for some cases, the boat form is preferable. The new six-membered cyclohexanol derivative 2 has been obtained by the synthesis of (E)-1-(bromophenyl)-3-phenylpropen-2-one (1). The NMR and quantum-chemical conformational analysis for the 2 have carried out, and its possible mechanism of formation was given.

Full text of DOI:10.1002/mrc.4377

Research article
Received: 5 June 2015
Revised: 20 September 2015
Accepted: 2 October 2015
Published online in Wiley Online Library: 2 November 2015
(wileyonlinelibrary.com) DOI 10.1002/mrc.4377
Synthesis of a new 1,2,3,4,5-pentasubstituted
cyclohexanol and determining its
stereochemistry by NMR spectroscopy
and quantum-chemical calculations
Ibrahim Mamedov,a* Rza Abbasoglu,b Musa Bayramova
and Abel Maharramova
The presence of substituents in cyclohexane can influence to the ratio of conformers; for some cases, the boat form is preferable.
The new six-membered cyclohexanol derivative 2 has been obtained by the synthesis of (E)-1-(bromophenyl)-3-phenylpropen-2-
one (1). The NMR and quantum-chemical conformational analysis for the 2 have carried out, and its possible mechanism of forma-
tion was given. Copyright © 2015 John Wiley & Sons, Ltd.
Keywords: chalcone; cyclohexanol; conformation; NMR
NOESY: pulse program = noesyph, digital resolution = 1.97 Hz,
Introduction
SWH = 2610 Hz, TD = 1 K, SI = 512 K, 900 pulse-length = 10 μs,
The chemistry of chalcones is of great scientific interest and has been
generated intensive studies in the organic chemistry. Chalcones are
efficient synthones in building novel heterocycles and cyclohexane
derivatives with good pharmaceutical properties, such as antimicro-
bial, antibacterial, antifungal, anticancer, antitubercular, antiviral,
anti-inflammatory, antihyperglycemic, and other activities.[1–13]
The NMR is a very important analytical method for identifying the
structure of organic molecules and studies of dynamic processes in
different solutions.[14–27] We have applied NMR and quantum-
chemical calculations methods to the cyclohexane derivative of
the chalcone 1 to obtain insight into the three-dimensional struc-
ture of this system.
PL1 = 3 dB, ns = 16, ds = 8, d1 = 1.5 s, and d8 = 0.3 s.
ROESY: pulse program = roesyph, digital resolution = 1.49 Hz,
SWH = 3063 Hz, TD = 2 K, SI = 512 K, 900 pulse-length= 10 μs,
PL1 = 3 dB, ns= 16, ds= 4, and d1= 2 s.
HSQC: pulse program = hsqcetgp, digital resolution= 2.95 Hz,
SWH = 3019 Hz, TD= 1 K, SI= 512 K, 900 pulse-length = 10 and 9 μs,
PL1 = 3 dB, PL2 = 1.5 dB, ns= 2, ds = 16, and d1= 1.5s.
HMBC: pulse program= hmbcgppndqf, digital resolution=
0.97 Hz, SWH = 4006 Hz, TD= 4 K, SI = 512 K, 900 pulse-length = 10
and 9 μs, PL1= 3 dB, PL2= 1.5dB, ns= 16, ds = 2, and d1 = 1.5 s.
The NMR-grade DMSO-d6 (99.7%, containing 0.3% H2O),
acetone-d6 (99.7%), and CCl4 (100%, several drops of D2O were
added for the lock signal as external standard) were used for the
solutions of 1 and 2.
Experimental section
Quantum-chemical calculation has been carried out by the DFT
B3LYP/6-31G and B3LYP/6-31G (d,p) methods.
Mass spectra were recorded on an Esquire 6000 (Bruker) using
positive electrospray ionization.
NMR spectra
The NMR experiments have been performed on a Bruker FT NMR
spectrometer AVANCE 300 (Bruker, Karlsruhe, Germany) (300 MHz
1
for H and 75 MHz for 13C) with a BVT 3200 variable temperature
The purity and the structure of the synthesized compounds were
confirmed by layer chromatography (Silufol UV-254, 0.1-mm silica
gel plates, iodine vapor as visualizing agent, and eluent 5 : 2
unit in 5-mm sample tubes using Bruker standard software (Top-
Spin 3.1). The 1H and 13C chemical shifts were referenced to inter-
nal tetramethylsilane; the experimental parameters for 1H are as
follows: digital resolution = 0.23 Hz, SWH = 7530 Hz, TD = 32 K,
SI = 16 K, 900 pulse-length = 10 μs, PL1 = 3 dB, ns = 1, ds=0, and
d1 = 1 s and for 13C as follows: digital resolution = 0.27 Hz,
SWH = 17985 Hz, TD = 64 K, SI = 32 K, 900 pulse-length = 9 μs,
PL1 = 1.5 dB, ns = 100, ds = 2, and d1 = 3 s.
1
hexane/ethyl acetate), 1D/2D NMR spectra (Figs. S1–S9). The H
and 13C NMR data of compound 2 were given in Table 1.
*
Correspondence to: Ibrahim Mamedov, Baku State University, Chemical Faculty,
NMR Laboratory, Z. Khalilov 23, Baku, Azerbaijan. E-mail: bsu.nmrlab@list.ru
a Chemical Faculty, NMR Laboratory, Baku State University, Z. Khalilov 23, Baku,
Azerbaijan
COSY: pulse program = cosygpqf, digital resolution = 1.97 Hz,
SWH = 2610, TD = 1 K, SI = 512, 900 pulse-length = 10 μs,
PL1 = 3 dB, ns = 4, ds = 16, and d1 = 1 s.
b Department of Chemistry, Karadeniz Technical University, 61080, Trabzon, Turkey
Magn. Reson. Chem. 2016, 54, 315–319
Copyright © 2015 John Wiley & Sons, Ltd.

I. Mamedov et al.
Synthesis
A mixture of 4-bromoacetophenone (1.99 g, 0.01 mol) and benz-
aldehyde (1.06 g, 0.01 mol) in 20 ml ethanol and 0.5 and 5 ml of
10–60% sodium (or potassium) hydroxide solution was added
and stirred at room temperature for 3 h. The precipitate formed
was collected by filtration and recrystallized in ethanol.
In the presence of 0.5 and 5 ml of 10–40% sodium or potassium
hydroxide solution, a white compound 1 is obtained, which is
known in the literature[28]; in the presence of 5 ml of 50% and
60% sodium or potassium hydroxide solution, a new pale pink com-
pound 2 is obtained. Both compounds were obtained as powders;
the yield of the chalcone 1 is 67–90% (Scheme 1, Table 2). the new
product 2 is 26–37%, M.p. 180–183 °C (Table 2), electrospray
ionization–MS: m/z [M+ H]+ 773, 697, 555, 502, 413, 360, 307.
Results and discussion
The synthesis of the chalcone 1 and its halogenated cyclohexane
derivative 2 are given in Scheme 1 and in the experimental section.
In 1896, Kostanecki and Rossbach prepared two compounds
(Kostanecki’s triketone) for the first time by the reaction of benzal-
dehyde and acetophenone in a 2 : 3 molar ratio in concentrated al-
coholic NaOH with melting points of 198 °C and 256 °C,
respectively.[29] In 1990, Vasilyev’s research group confirmed the
three-dimensional molecular structure of 1,2,3,4,5-pentasubstituted
cyclohexanol by a single-crystal X-ray diffraction analysis.[30]
Later on, Kessler, Gareth, and Colin’s group investigated the ste-
reochemistry of pyridinyl-containing analog of Kostanecki’s
triketone by X-ray, 2D NMR spectroscopy.[31,32] In 2006, Z. Shan
reported on synthesis, X-ray, NMR studies, and formation mecha-
nism of polysubstituted cyclohexanols in the presence of solid
NaOH and K2CO3.[33]
In the previously mentioned work[29,33], benzaldehyde (or its
substituted derivatives) and acetophenone were used as a
starting materials. In the present work, we decided to take 4-
bromoacetophenone, benzaldehyde, and different concentra-
tion (10–60%) of alcoholic NaOH and KOH solutions.
However, our studies confirmed that types of substrate (in our case
4-bromoacetophenone) do not influence to the reaction product
(influence to the yield), and new six-membered Kostanecki triketone
derivative 2 was obtained at high concentrations of bases (Table 2).
As seen from the obtained data, the yield of triketone was reduced
significantly (26–37%), but in previously indicated works[29,33] for
some triketone derivatives, yield was made up higher than 90%.
A new product 2 was synthesized by the presence of 5 ml, 50%
and 60% base catalyst. Possible formation mechanism of 2 in the
presence of a base catalyst is given in Scheme 2. As can be seen
from the Scheme 2, after formation of compound 1, interaction of
obtained chalcone with the carbanion A occurs in the second step.
In the third step, a second molecule of chalcone 1 reacts with the
newly formed carbanion B, and the carbanion C is obtained as a re-
sult of cyclization. In the last step, migration of hydrogen from the
medium occurs, and the six-membered cycle is formed.
For the investigation of the stereochemistry of compound 2, we
have applied NMR and quantum-chemical methods (Figs. 1 and 2,
Figs. S6 and S7). Calculated relative energies of conformers are
given in Table 3.
As seen from the 2D NOESY and ROESY (Fig. S6 and S7), spectra
spatial interactions between the 2A-2B, 2A-3, 2B-4, 2B-6, 2B-Ar, 3-5,
3-OH, 3-Ar, 5-OH, 5-Ar, 4-6, 4-Ar, OH-Ar, 6-Ar protons have been ob-
served inside the molecule.
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Magn. Reson. Chem. 2016, 54, 315–319

The NMR is an important at studiying of dynamic processes in solutions
Scheme 1. Synthesis of the chalcone 1 and its cyclohexanol derivative 2.
Table 2. Yield of compounds (1 and 2) at the presence of KOH and NaOH
NaOH
KOH
ml
%
yield
ml
%
yield
ml
%
yield
ml
%
yield
1
2
1
2
1
2
1
2
0.5
0.5
0.5
0.5
0.5
0.5
10
20
30
40
50
60
67
68
68
71
71
73
—
—
—
—
—
—
5
5
5
5
5
5
10
20
30
40
50
60
85
85
86
86
7
—
—
—
—
26
33
0.5
0.5
0.5
0.5
0.5
0.5
10
20
30
40
50
60
71
74
74
75
76
76
—
—
—
—
—
—
5
5
5
5
5
5
10
20
30
40
50
60
89
90
90
89
5
—
—
—
—
31
37
—
—
Scheme 2. Formation mechanism of the compound 2 at the presence of base catalyst.
As we can be seen in the Table 3, the most stable conformer is
a chair (A) with zero relative energy. NMR investigations in
acetone-d6 and diluted CCl4 solutions have confirmed the forma-
tion of intramolecular hydrogen bond between the OH and O = C
groups (1H hydroxyl proton signal in acetone-d6 at δ = 4.92 ppm
and in diluted CCl4 at the 4.9ppm was observed). The stability
of the chair conformation (A) may be connected with the forma-
tion of intramolecular hydrogen bond between the hydroxyl and
Magn. Reson. Chem. 2016, 54, 315–319
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I. Mamedov et al.
Figure 1. The chair A and boat B conformations for 2 calculated by the DFT B3LYP/6-31G and B3LYP/6-31G(d,p) methods.
Figure 2. Different type of chair (A) conformation for the 2 calculated by the DFT B3LYP/6-31G and B3LYP/6-31G(d,p) methods.
Table 3. The calculated relative energies of conformers, (kcal/mol)
Different
Calculation methods
conformers
B3LYP/6-31G
B3LYP/6-31G(d,p)
Chair (A)
Boat (B)
A-I
0.000
5.654
7.027
7.861
0.182
7.009
23.397
2.341
9.829
7.072
0.000
6.307
6.891
7.608
0.295
6.883
21.642
3.319
10.330
7.568
A-II
A-III
A-IV
A-V
A-VI
A-VII
A-VIII
Figure 3. The calculated distance (Å) between the O-HÁÁÁO by the DFT
B3LYP/6-31G and B3LYP/6-31G(d,p) methods.
the carbonyl groups (Fig. 3). The O-HÁÁÁO distances have been cal-
culated by the DFT B3LYP/6-31G, B3LYP/6-31G(d,p) methods and
equal 1.848 and 1.849 Å, respectively.
The preferred chair conformation for the six-membered ring
[4-(4-bromophenyl)-4-hydroxy-2.6-diphenylcyclohexane-1.3-diyl)
bis(4-bromophenyl)methanone, 2] was confirmed by 2D NOESY,
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The NMR is an important at studiying of dynamic processes in solutions
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