Synthesis and examination of antimicrobial properties of aminomethylated derivatives C6-C7 of alicyclic diols

Article abstract of DOI:10.1134/S1070427209070180

Synthesis of C₆-C₇ alicyclic diols was studied by a catalytic oxidation of cyclohexene, norbornene and their methyl derivatives in the presence of heterogenized molybdenum-containing catalysts. By a triple condensation of the diols with formaldehyde and secondary amines a synthesis of their aminomethylated derivatives with various substituents at nitrogen atom was examined. Antimicrobial properties of the synthesized amino alcohols in M-10 oil as additives with fungicidal and bactericidal activities were studied.

Full text of DOI:10.1134/S1070427209070180

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2009, Vol. 82, No. 7, pp. 1255−1262. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © Kh.M. Alimardanov, O.A. Sadygov, E.T. Suleimanova, N.A. Dzhafarova, M.Ya. Abdullaeva, N.R. Babaev, 2009, published in
Zhurnal Prikladnoi Khimii, 2009, Vol. 82, No. 7, pp. 1159−1166.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Synthesis and Examination of Antimicrobial Properties
of Aminomethylated Derivatives
C6−C7 of Alicyclic Diols
Kh. M. Alimardanov, O. A. Sadygov, E. T. Suleimanova, N. A. Dzhafarova,
M. Ya. Abdullaeva, and N. R. Babaev
Institute of the Petrochemical Processes, Azerbaijanian Academy of Sciences, Baku, Azerbaijan
Received December 3, 2008
Abstract—Synthesis of C6−C7 alicyclic diols was studied by a catalytic oxidation of cyclohexene, norbornene and
their methyl derivatives in the presence of heterogenized molybdenum-containing catalysts. By a triple condensation
of the diols with formaldehyde and secondary amines a synthesis of their aminomethylated derivatives with
various substituents at nitrogen atom was examined. Antimicrobial properties of the synthesized amino alcohols
in M-10 oil as additives with fungicidal and bactericidal activities were studied.
DOI: 10.1134/S1070427209070180
Alicyclic amino alcohols containing alkyl-, aryl-, and
heterocyclic substituents at nitrogen atom are promising
intermediates of organic and petroleum synthesis whose
structural features determine their rich functional
capacity as monomers and biologically active substances
employed in pharmaceuticals of various functions [1–3].
These compounds are of interest due to the presence of
similar structural moieties in composition of many natural
biologically active substances [4, 5].
by induced oxidation of the corresponding cycloolefins
with hydrogen peroxide in the presence of acetic acid
and heterogenic catalysts obtained on the basis of
bentonite, kaolin, and halides or oxyhalides of metalls
of VI–VIII groups of the periodic system, followed
by aminomethylation of the reaction products without
previous separation of oxidate, and also at a research
of the antimicrobial properties of the synthesized
compounds.
Unlike amino alcohols of aliphatic and aromatic series
[6–8] similar derivatives of alicyclic series [9, 10] attract
significantly smaller attention. Data on the synthesis
of aminomethylene derivatives from cyclohexane and
norbornane diols, and on the investigation of their
biological properties are practically lacking.
EXPERIMENTAL
Starting cyclohexene and 1-methylcyclohexene were
prepared by cyclohexanol and 3-methylcyclohexanol-1
dehydration at 220–250°Сon γ-Al2О3. Bicyclo[2,2,1]hept-
2-ene and its 5-methyl derivative we synthesized by
condensation of cyclopentadiene with ethylene and
propylene with the aid of a known technique [3].
It is known that the simultaneous presence in a
molecule of amino- and hydrosubstituents imparts to
them antioxidation and antimicrobial properties [11].
Nowadays when machines and mechanisms are improved
a protection of applied oils, fuels, and composed polymeric
and other materials from biodamages is actual [12].
Samples of catalysts we impregnated with a mixture
of bentonite, kaolin, and aqueous or alcoholic solutions
of МоСl5, МоОВr3, WCl6, CrO2Сl2, СоВr2, followed
by their carbonization in 4-vinylcyclohexene flow at
500–550°С in the course of 4 h.
Our paper is aimed at a synthesis of N-substituentd
amino alcohols of cyclohexane and norbornane series
1255

1256
ALIMARDANOV et al.
The cycloolefin oxidation was conducted in glass
possibly caused by partial introduction of coal moieties in
a composition of compounds of transition metals, and by
a formation of more active form of a catalytic complex.
thermostat equipped with a magnetic stirrer at 70–80°С
in the presence of the above catalysts. The reaction
course was monitored by chromatography and chemical
techniques (permanganate- and iodometric titration).
After the reaction completion the organic and aqueous
layers were separated, the latter layer was three times
extracted with toluene. An extract and the organic layer
were mixed, and first at 75–85°C and then at 100–105°C
in a glass reactor equipped with a nozzle were subjected
to aminomethylation with formaldehyde and secondary
amines (under conditions of Mannich reaction). The
reaction mass after toluene distillation and cooling
was maintained for a day, and then aminomethylated
derivatives of the corresponding diols were isolated by
vacuum distillation.
Using freshly prepared samples in the reaction course
upon substrate oxidation a partial transition of salts from
the catalyst composition into a liquid phase occurs. After
removal of the used catalyst a rate of further oxidate
oxidation is strongly decreased and consists 10–15%
of the oxidation rate in the case of the presence of the
catalyst.
The salt transition in the oxidate proceeds more
intense use of a non-carbonized catalyst. In this case
apparently salt molecules weakly attached to a contact
surface pass in the solution. Due to a treatment of
these samples under oxidation conditions for 3–4 h the
transition of chlorides and bromides in a solution is
practically stopped.
IR spectra of the synthesized compounds were
recorded on a UR-20 spectrometer in a range of 400–
3600 cm–1,1H NMR spectra, with Jeol-FT80Ainstrument
(80 MHz), solvent CCl4, internal reference HMDS. The
purity of the synthesized compounds was determined by
thin layer chromatography TLC on Silufol UV-254 plates
in the systems of the solvents [benzene : diethyl ether =
(3–5) : 1, a developer iodine].
Oxidate composition obtained in the presence of the
developed catalytic systems is practically identical with
compositions prepared with the aid of homogeneous
catalysts [15, 16]. Main products are epoxides, diols and
their monoacetates. In some cases there are unsaturated
alcohols and ketones in the catalysate. The molybdenum-
containing samples (MoOBr3, MoCl5) are the most
active and selective among the synthesized catalysts.
The oxidation of other unsaturated hydrocarbons was
performed in the presence of these samples of the catalysts
according to the scheme:
Antimicrobial properties of the synthesized
compounds were determined by GOST 9,052–88
and 9,082–77 (RF State Standard). Microoraganisms:
bacterial (Mycobacterium lacticola, Psendomonas
aeruginosa), fungicidal (Aspergillus niger, Clodo-
sporium resinac), yeast (Candida tropicalis) were used
as test-cultures. The noted microorganisms were grown
at 28 ± 2°С in a special thermostat with 90–100%-
moisture: fungi for 5−6 days; bacteria for 2–3 days.
Beef-extract agar (BEA) and wort-agar (WA) were used
as nutrient media for bacteria cultures, and fungi and
yeast cultures, respectively. 8-Oxyquinoline and sodium
pentachlorophenolate were used as references.
CH
R
O
CH
CH
cat.,
in dioxane
in diocane
CO(NH) , H2O2,
2
R
or H
2O2
CH
CH OH
CH OH
R
–IV
I
I –
IV
Catalytic oxidation of the cycloolefins by hydrogen
peroxide was carried out in a heterophase system
liquid−liquid in the presence of powdery heterogenized
catalysts which react readily with hydrogen peroxide
forming peroxy compounds of various compositions
and stability [14]. The experimental results on catalyst
selection are presented in Table 1.
where R is cyclohexene (I), 3-methylcyclohexene
(II), becyclo[2,2,1]hept-2-ene (III), 5-methylbicyclo-
[2,2,1]hept-2-ene (IV), the corresponding vicinal dioles
(Ia)–(IVa). Experimental results are listed in Table 2.
The synthesis of the corresponding amino alcohols
was carried out from the condensation of the isolated
diols, and also oxidate with formaldehyde and secondary
amines of various composition and structure (according
to Mannich reaction).
The results of the experiments in the presence of both
carbonized and non-carbonized samples of catalysts were
listed in Table 1. As shown in these data the carbonized
samples manifest higher activity in oxidation that is
Optimal product yields of aminomethylation of
cyclohexane diol are attained at 70–80°С, of norbornane
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SSYNTHESIS AND EXAMINATION OF ANTIMICROBIAL PROPERTIES
1257
Table 1. Activity of catalyst in the course of oxidation of cyclohexene with hydrogen peroxide. Temperature 70°C, reaction time
1 h, molar ration cyclohexene : СН3СООН : active oxygen [O] = 1: 0.2 : 1.2
a A support is nAl2O3 · mSiO2–bentonite : kaolin = 5 : 1. b Carbonized catalyst.
Table 2. Induced oxidation of cycloolefins by hydrogen peroxide in the presence of carbonized МоCl5/nAl2O3·mSiO2. Temperature
80°C, reaction time 4 h, molar ratio of cycloolefin : СН3СООН : active oxygen [O] = 1 : 0.2 : 1.2
protons Н5, Н6 we can conclude that the synthesized
compounds have the endo-configuration. In a region
δ 1.31 and 1.56 ppm there are Н7 protons and Н7
diol at 100–105°С, under an equimolar ratio of reagents
and reaction time of 4–6 h (Table 3).
anti
sin
Structure of the synthesized diols and their amino-
methylated derivatives was determined by IR and
protons; С2 and С3 signals manifest themsemves as
doublet at δ = 3.26 ppm with coupling constant J2,3
=
1
1H NMR spectroscopy [17, 18]. In H NMR spectrum
4.5–4.7 Hz. Proton signals of two hydroxy groups reveal
themselves in the region 4.81 ppm (br.s), proton signals
at С1 and С4, in the region 1.52 ppm (d). Proton signals of
methylbicyclo[2.2.1]heptane-2,3-diol (IVa) are identical
with signals of compound IIIa. Protons of methyl group
are manifested at δ = 1.09 ppm (s), proton signal at C5
bearing the methyl group is shifted down field (δ = 1.61
ppm), signals of two protons at C6 shift up field and reveal
themselves at δ = 1.25 and δ = 1.50 ppm.
of bicyclopentadiol-2,3 (IIIa) in a region of strong fields
appears a doublet of doublets signal with chemical shift
at δ = 1.38 ppm corresponding to endo-protons, and triplet
signal δ = 1.57 ppm corresponding to exo-protons at С5
and С6 atoms. On the basis of the coupling constants
(J6,6 = 12.2–12.5, J5,6 endo = 5.0–5.3, J5,6 exo = 9.5–9.7
Hz) since the high coupling constant corresponds to exo-
protons Н5, Н6 and the low coupling constant, endo-
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1258
ALIMARDANOV et al.
Table 3. Yield and composition of products of aminomethylation
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SSYNTHESIS AND EXAMINATION OF ANTIMICROBIAL PROPERTIES
1259
We established that the reaction direction and the
product composition depend mainly on the reaction
temperature. Reaction proceeds with equimolar ratios of
the reagents, in a temperature range of 65–70°С in the
course of 4−5 h in general with the formation of amino
alcohols [14]. More stringent conditions (an increase in
temperature up to 100–110°С and in reaction time up
to 5–6 h) result in enhancement of aminomethylation
of alicyclic diols. This reaction route, possibly, occurs
through a stage of formation of intermediate with
dioxolane moiety then attacked by the molecule of the
secondary amine with formation of the corresponding
six-membered complex. Decomposition of latter yields
aminomethylated derivatives С6–С7 of alicyclic diols
according to Mannich reaction.
1570, 1590 and 770–730, 690 см–1 typical of aminophenyl
radical.
In 1H NMR spectra of amino alcohols Vа–Vf–VIIа–
VIIf there is a wide singlet at 4.81 ppm attributed to OH-
group. In spectra of products Vc−VIIc appeared also a wide
singlet 4.78 ppm typical of hydroxy groups of oxyethylene
moieties at nitrogen atom. Proton of CHOH-group at
cyclohexyl radical of compounds Va−Vf, VIa−VIf is
characterized by a triplet at 3.40–3.48 ppm in compounds
VIIа–VIIf, and by doublet of doublets at 3.99–3.40
ppm. Spectra of amino alcohol Va−VIIIa possess
singlet at 2.28 ppm, of compounds Vc−VIIIc, a singlet
at 1.06–1.10 ppm attributed to protons of СН3-groups.
Protons –NСН2СН2-group of amino alcohols Ib–IVb
are characterized by a doublet at 2.42 ppm, Vc–VIIIc,
by a doublet of doublets at 2.56–2.64 ppm. Spectra of
compounds Id–IVd contain doublets at 1.42 and 2.26 ppm
characterizing the protons of СН2-group of piperidine and
morpholine moieties, respectively.
H
C
OH
HNR1R2
(CH2)n
O
CH2
+
+
OH
C
Spectra of amino alcohols Vf−VIIIf possess a doublet
at 5.16 ppm and multiplets in a region of 6.43–7.08
ppm attributed to protons of –ОСН2N= and of aromatic
moieties, respectively.
H
–
Ia IVa
H
O
Synthesized compounds with concentrations 1 and 2
wt% were examined as antimicrobial additives to an engine
oil M-10. Experimental results are listed in Table 4.
~
H
~
_
(CH 2)n
CH2
H2O
NR1R2
O
As shown in the presented data all studied amino
methylated derivatives of alicyclic diols possess fungi-
cidal activity. A value of an inhibition area of a fungus
growth in dependence on the compound structure and its
concentration is on the average 0.7−1.1 cm (at 1 wt %
concentration) and 1.3–2.1 cm (at 2 wt % concentration).
H
H
C
OH
O
R1
R2
)
(CH2
n
N
CH2
C
Phenylaminomethoxy- and morpholinemethoxy-
substituentd cyclohexane-, methylcyclohexane-, and
norbornane diols are characterized by fungicidal prop-
erties and are not worse than 8-oxyquinoline (reference)
according to their values. As shown in Table 4, 8-
oxy-quinoline does not possess fungicidal activity at 1
wt% concentration, but the fungi growth is inhibited
on 2 wt% concentration. These data manifest that
the examined compounds are not worse than sodium
pentachlorophenolate (reference) in their fungicidal
properties. As regards the used oil M-10 it is unstable
for fungi and bacteria. Results of comparative researches
show that iminomethylene derivatives of alicyclic
diols are of practical interest, and can be applied as
antimicrobial additives to lubricating oils
H
R1=R2=CH3 Vа–VIIIа; R1=R2=C2H5 Vb–IIIb;
R1=R2=CH2СН2ОН Vc–VIIIc; R1 + R2 = –(СН2)5
Vd–VIIId; R1 + R2 = [–(СН2)2]2О Ve–VIIIe; R1 = H,
R2 = –С6Н5 (Vf)–(VIIIf).
In the IR spectra of mono and bicyclic amino alcohols
the absorption bands in a region 3615 and 1150 cm–1
are attributed to ОН-group at tertiary carbon atom. For
amino alcohols Vc–VIIc absorption bands were found at
frequencies 3630 and 1250 cm–1, attributed to primary
СН2–ОН-group of alkyl radical. In the IR spectra of
compounds Vf−VIIf there exist the vibration in a region
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ALIMARDANOV et al.
Table 4. Experimental results of antimicrobial properties of aminomethylated derivatives of alicyclic diols in an engine
oil M-10
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SSYNTHESIS AND EXAMINATION OF ANTIMICROBIAL PROPERTIES
1261
Table 4. (Contd.)
Antimicrobial action of the synthesized compounds
essentially depends on the nature of substituents at
nitrogen atom and increases in series.
of cyclohexane- and norbornane diols, and it was stated
that these compounds of 1−2 wt % concentration in the
engine oil possessed high fungicidal and bactericidal
activity relative to mycelial fungi.
CONCLUSIONS
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