Synthesis and inhibitory activity of alkyl(hydroxyaryl)amines

Article abstract of DOI:10.1007/s11172-007-0174-1

The reaction of ω-(4-hydroxyaryl)haloalkanes with various nitrogen-containing agents afforded primary, secondary, and tertiary amino derivatives of 2,6-dialkylphenols. For the compounds synthesized, the reaction rate constants with peroxide radicals were

Full text of DOI:10.1007/s11172-007-0174-1

Russian Chemical Bulletin, International Edition, Vol. 56, No. 6, pp. 1149—1155, June, 2007
1149
Synthesis and inhibitory activity of alkyl(hydroxyaryl)amines*
a
a
a
b
O. I. Dyubchenko,a V. V. Nikulina, E. I. Terakh, A. E. Prosenko, and I. A. Grigor´ev
ꢀ
aResearch Institute of Antioxidant Chemistry, Novosibirsk State Pedagogical University,
28 ul. Vilyuiskaya, 630126 Novosibirsk, Russian Federation.
Fax: +7 (383) 268 1856. Eꢀmail: chemistry@ngs.ru
bN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752. Еꢀmail: grig@nioch.nsc.ru
The reaction of ωꢀ(4ꢀhydroxyaryl)haloalkanes with various nitrogenꢀcontaining agents
afforded primary, secondary, and tertiary amino derivatives of 2,6ꢀdialkylphenols. For the
compounds synthesized, the reaction rate constants with peroxide radicals were measured for
cumene and methyl oleate oxidation. The total inhibitory activity in the model reactions of
thermal autooxidation of lard and hexadecane was studied. The rate constants of alkyl(hydrꢀ
oxylaryl)amines are the same as those of the corresponding alkylphenols, whereas the total
inhibitory activity of some alkyl(hydroxylaryl)amines exceeds substantially that for alkylphenols.
Key words: 2,6ꢀdialkylphenols, ωꢀ(4ꢀhydroxyaryl)haloalkanes, alkyl(hydroxylaryl)amines,
aminoalkylphenols, antioxidation activity, peroxide radicals, total inhibitory activity.
Alkyl(hydroxyaryl)amines (aminoalkylphenols) are
highly efficient inhibitors for free radical oxidation of variꢀ
ous organic substrates. According to patent data,1—4 they
can be used as stabilizers of polymeric materials, rubbers,
lubricants, and diesel and jet fuels. In addition, alkyl(hydrꢀ
oxyaryl)amines and their salts possess a high spectrum of
biological activity, in particular, they manifest antiphloꢀ
gistic,5 antiarrhythmic,6 radioprotective, and antitumor7
properties. At the same time, regularities of changes in the
antioxidation activity of alkyl(hydroxyaryl)amines deꢀ
pending on their structure are insufficiently studied: these
data are presented only in few studies8—12 devoted preꢀ
dominantly to benzylic compounds.
comparatively their antioxidation activity in various model
systems.
Results and Discussion
Tertiary amines 1—3 were synthesized by the reacꢀ
tions of the corresponding ωꢀ(4ꢀhydroxyaryl)chloroꢀ
alkanes 7 with dialkylamines in yields up to 90%
(Scheme 1).
Scheme 1
In the present study, we synthesized structurally reꢀ
lated series of alkyl(hydroxyaryl)amines 1—6 and studied
7: R = R´ = But, n = 2 (a), 3 (b), 4 (c); R = But, R´ = H, n = 3 (d);
R = R´ = Me, n = 3 (e); R = R´ = H, n = 3 (f);
R = R´ = cycloꢀC6H11, n = 3 (g); R = But, R´ = Me, n = 3 (h);
R = R´ = But, n = 5 (i)
R = R´ = But, n = 2 (a), 3 (b), 4 (c); R = But, R´ = H, n = 3 (d);
R = R´ = Me, n = 3 (e); R = R´ = H, n = 3 (f);
Secondary amines 4a—c and 5a—c were synthesized
similarly in 60—72% yields by the reactions of chloroꢀ
alkanes 7 with methylꢀ and propylamines.
Primary amines 6а—с were synthesized from bromoꢀ
alkanes 8а—с through intermediate alkylphthalimides
9а—с (Scheme 2).
R = R´ = cycloꢀC6H11, n = 3 (g); R = But, R´ = Me, n = 3 (h);
R = R´ = But, n = 5 (i)
R″ = Me (1a—i, 4a—c), Et (2a—f), Pr (3a—d, 5a—c), H (6a—c)
* Dedicated to the memory of Academician N. N. Vorozhtsov
on the 100th anniversary of his birth.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1107—1112, June, 2007.
1066ꢀ5285/07/5606ꢀ1149 © 2007 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Dyubchenko et al.
Scheme 2
Oxygen volume/mL
0.25
1
2
[O2]/[RH]•105
2.8
0.20
0.15
0.10
0.05
2.4
2.0
1.6
1.2
3
4
1.2
2.0 –ln(1 – t/τ)
0
10
20
30
40
t/min
n = 2 (a), 3 (b), 4 (c)
Fig. 1. Kinetic curves of oxygen absorption in initiated cumene
oxidation at 60 °C in the presence of TMP (1) and amine 1i (2);
their anamorphoses are given in inset (3 and 4, respectively).
The compositions and structures of aminoalkylphenols
1—6 synthesized were confirmed by elemental analysis
data and spectral characteristics.
Aminoalkylphenols 1—6 contain two functional
groups, namely, the phenol and alkylamine groups, caꢀ
pable of inhibiting processes of free radical oxidation. The
phenolic OH group acts as an inactivator of active radiꢀ
cals, and the alkylamine group can decompose peroxides
to form Nꢀoxides11 or regenerate phenol due to the
aminoperoxide radicals formed by oxidation.13
The antiradical activity of the phenol fragments of
compounds 1—6 was studied under the conditions of
cumene and methyl oleate oxidation initiated by AIBN.
The total inhibitory activity was determined for the therꢀ
mal autooxidation of hexadecane and lard.
Earlier12 synthesized dimethyl(3ꢀR1ꢀ5ꢀR2ꢀ4ꢀhydroxyꢀ
benzyl)amines 10а—d (R1 = R2 = But (a); R1
But, R2 = Me (b); R1 = R2 = Me (c); R1 = R2
cycloꢀC6H11 (d)), 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol
(ionol), 2ꢀtertꢀbutylꢀ4ꢀmethylphenol (TBMP), 2,4,6ꢀ
trimethylphenol (TMP), 2,6ꢀdicyclohexylꢀ4ꢀmethylꢀ
phenol (DCHMP), and 4ꢀmethylphenol (MP) were used
as reference antioxidants.
The antiradical activity of the compounds studied was
characterized by the rate constants of their reactions with
the peroxide radicals of cumene and methyl oleate (k).
Oxygen volume/mL
[O2]/[RH]•103
2.0
1.5
1.0
0.5
1
3
4
2
1
0
3
2
0
0.6
1.2
–ln(1 – t/τ)
=
=
0
20
40
60
80
100
120
t/min
Fig. 2. Kinetic curves of oxygen absorption in initiated methyl
oleate oxidation in chlorobenzene at 60 °C in the presence of
amine 1g (1) and ionol (2); their anamorphoses are given in
inset (3 and 4, respectively).
stants of the peroxide radicals with molecules of the inꢀ
hibitor and oxidized substrate, respectively; τ is the inꢀ
duction period; t is time; [RH] is the substrate concentraꢀ
tion in the sample.
This indicates that the reactions of cumene and methyl
oleate oxidation are inhibited according to the commonly
accepted scheme14 and the k rate constant can be deterꢀ
mined by Eq. (1).
ArOH + ROO•
ArO• + ROOH
The initial regions of the kinetic curves of oxygen
absorption for AIBNꢀinitiated cumene and methyl oleate
oxidation in the presence of the compounds under study
(Figs 1 and 2) are well linearized in the coordinates of the
equation
The k1/k ratio was determined from the slope ratios
of the straight lines in the coordinates of the plot of
∆[O2]/[RH] vs. –ln(1 – t/τ). The absolute values of the
k constant for cumene oxidation were calculated using
∆[O2]/RH = –k1/kln(1 – t/τ),
(1)
where ∆[O2] is the amount of absorbed oxygen referred to
the sample volume; k and k1 are the reaction rate conꢀ

Inhibitory activity of alkyl(hydroxyaryl)amines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1151
Table 1. Parameters of the antioxidation activity of 2ꢀR1ꢀ4ꢀR2ꢀ6ꢀR3ꢀsubstituted phenols
Comꢀ
pound
R1
R2
R3
k•10–4/L mol–1 s–1
τ/min
Cumene Methyl oleate Hexadecane
Lard
1a
1b
1c
1d
1e
1f
1g
1h
1i
2b
3b
4b
But
(CH2)2NMe2
(CH2)3NMe2
(CH2)4NMe2
(CH2)3NMe2
(CH2)3NMe2
(CH2)3NMe2
(CH2)3NMe2
(CH2)3NMe2
(CH2)5NMe2
(CH2)3NEt2
(CH2)3NPr2
(CH2)3NHMe
(CH2)3NH2
CH2NMe2
CH2NMe2
CH2NMe2
CH2NMe2
Ме
But
2.5 0.3
2.6 0.2
3.0 0.2
2.9 0.2
1.4 0.2
3.4 0.1
—
3.8 0.2
4.0 0.3
—
2.4 0.2
2.3 0.2
2.9 0.2
3.0 0.2
2.2 0.2
4.2 0.5
3.8 1.0
5.1 0.3
—
2.6 0.4
3.6 0.3
4.7 0.2
2.0 0.2
139
135
142
111
76
7
72
106
130
88
63
92
87
119
97
76
71
7
80
5
7
5
5
5
2
5
5
5
5
5
5
5
5
5
5
5
2
5
5
5
5
288
334
435
143
123
51
143
245
470
307
277
234
254
110
150
122
130
15
5
But
But
2.5 0.3
2.4 0.2
9.6 0.2
13.8 3.0
1.7 0.2
11.4 2.0
13.7 3.3
—
2.3 0.3
2.0 0.4
2.7 0.3
2.5 0.3
2.0 0.4
11.6 1.0
14.6 3.3
18.1 3.0
1.5 0.2
2.2 0.6
10.4 1.2
11.7 5.8
9.3 0.2
5
5
5
5
5
6
5
5
5
6
5
8
5
5
5
5
2
5
5
5
5
But
H
Ме
H
But
But
Ме
H
cycloꢀC6Н11
cycloꢀC6Н11
But
Ме
But
But
But
But
But
But
But
But
6b
But
But
10a
10b
10c
10d
MP
Ionol
TMP
DCHMP
TBMP
But
But
But
Ме
Ме
Ме
cycloꢀC6Н11
H
cycloꢀC6Н11
H
But
Ме
But
Ме
Ме
Ме
Ме
Ме
165
75
108
78
78
80
85
cycloꢀC6Н11
But
cycloꢀC6Н11
H
Note. The induction period for noninhibited lard is 15 min and that for hexadecane is 7 min.
the known15 k1 value (1.75 L mol–1 s–1). For the oxidaꢀ
tion of methyl oleate in chlorobenzene, the k1 value
(60.8 L mol–1 s–1) was estimated from the known k value
for ionol (2.6•104 L mol–1 s–1).16 The k constants found
by us (with the rootꢀmeanꢀsquare deviation) are presented
in Table 1.
It was shown for the 2,6ꢀdiꢀtertꢀbutylꢀsubstituted deꢀ
rivatives that the compounds bearing different alkylamine
groups (NMe2, NEt2, NPr2, NHMe, and NH2) and conꢀ
taining the nitrogen atom remote from the aromatic ring
at different distances are characterized in cumene and
methyl oleate oxidation by similar k rate constant values
close to the value for ionol.
At the same time, variations in the number and strucꢀ
ture of the substituents in the orthoꢀposition of the pheꢀ
nolic fragment were accompanied by changes in the k rate
constant values. For the oxidation of both cumene and
methyl oleate, the replacement of the tertꢀbutyl substituꢀ
ents in the orthoꢀposition by the methyl and cyclohexyl
groups in molecules of the compounds under study inꢀ
creased the k constant.
than that for methyl oleate oxidation ((3.4—5.1)•104
L mol–1 s–1).
The lower k rate constant values for the diꢀtertꢀbutylꢀ
substituted derivatives are due, evidently, to the steric
factor. It is most likely that the reactivity of orthoꢀdisubꢀ
stituted amines 1e,g,h and 10b—d, TMP, and DCHMP
in methyl oleate oxidation decreases because of hydrogen
bonding between the OH groups of the antioxidant molꢀ
ecules and ester groups of the methyl oleate molecules.17
For cumene oxidation, the k constant value in the
series 1b—1d—1f and ionol—TBMP—MP changes nonꢀ
monotonically: it increases on going from diꢀtertꢀbutylꢀ to
monoꢀtertꢀbutylꢀsubstituted phenols and decreases on goꢀ
ing from the latter to orthoꢀsubstituted phenols. This fact
can be due to the dual effect of the orthoꢀtertꢀbutyl subꢀ
stituents on the reactivity of phenols in the reaction with
peroxide radicals.14 On the one hand, these substituents
decrease the energy of the ArO—H bond cleaved in the
reaction. On the other hand, they create steric hindrance
for the interaction of the phenolic OH group with the
active radical. As a consequence, the intermediate monoꢀ
tertꢀbutyl substitution to the orthoꢀposition is most "faꢀ
vorable."
It is found that in both model systems the diꢀtertꢀ
butylꢀsubstituted derivatives are characterized by close k
values ((2.0—3.0)•104 L mol–1 s–1), whereas for less
shielded 2,6ꢀdialkylphenols the k value for cumene oxiꢀ
The antiradical activity decreased for the oxidation of
methyl oleate in the series of compounds 1b—1d—1f and
ionol—TBMP—MP. In this model system, orthoꢀsubstiꢀ
dation took higher values ((1.1—1.8)•105 L mol–1 s–1
)

1152
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Dyubchenko et al.
tuted amine 1f and MP exerted virtually no inhibition
effect on methyl oleate oxidation.
ring by two—five methylene units. These amines are of
interest for further investigation as potential antioxidants
used in practice.
According to the obtained data, aminoalkylphenols
synthesized exerted a pronounced inhibition effect on the
thermal oxidation of lard and hexadecane (see Table 1).
They increased the thermooxidation stability of these subꢀ
strates by 3.4—30 times, and the series of aminoalkylꢀ
phenols inhibited the oxidation process much more effiꢀ
ciently than the corresponding alkylphenols, which is asꢀ
sociated, most likely, with the bifunctional mechanism of
their antioxidation effect.11
The ability of aminoalkylphenols to inhibit lard and
hexadecane oxidation was found to be determined, to a
great extent, by the structure of their molecules: the strucꢀ
ture of the substituents at the nitrogen atom, the alkyl
chain length separating the phenol and alkylamine groups,
and the number and structure of the substituents in the
orthoꢀposition.
Experimental
ωꢀ(4ꢀHydroxyaryl)haloalkanes synthesized according to earꢀ
lier described methods18—20 were used as the starting synthons
for the preparation of aminoalkylphenols 1—6.
1H NMR spectra were recorded on a Bruker DRX500 specꢀ
trometer with a working frequency of 500.13 MHz, CDCl3 as
the solvent, and CHCl3 as the standard (δ 7.24). Melting points
were determined in a capillary on a PTP instrument (Industrial
Complex PO Khimlaborpribor, Russia).
The synthesis and characteristics of tertiary alkyl(hydroxyꢀ
aryl)amines 1a—d,f,g, 2a—c,f, and 3b and secondary amine 4b
have been described previously.11,21
Alkylphthalimide 9b and propylamine 6b were synthesized
according to a known procedure.21
It is shown that tertiary amine 1b has the highest
antioxidation activity in the oxidation of both lard and
hexadecane in the series of diꢀtertꢀbutylꢀsubstituted
aminoalkylphenols 1b—4b—6b bearing the nitrogen atom
with different numbers of alkyl substituents. The inhibiꢀ
tory activity of tertiary amines, in turn, decreased on going
from N,Nꢀdimethylꢀsubstituted amine 1b to its N,Nꢀdiꢀ
ethylꢀ and N,Nꢀdipropylꢀsubstituted analogs (2b and 3b,
respectively).
The inhibitory activity of 2,6ꢀdiꢀtertꢀbutylꢀsubstituted
pꢀaminoalkylphenols 1a—c,i and 10a containing differꢀ
ent carbon atoms in the alkyl chain for lard oxidation
increased with removing the nitrogen atom from the aroꢀ
matic ring. Among the compounds mentioned, the highꢀ
est antioxidant activity belongs to amine 1i, in which the
amino group is remote from the aromatic ring by five
methylene units. No distinct relation between the alkyl
chain length in the paraꢀposition and antioxidant activity
of these compounds was observed for hexadecane oxiꢀ
dation.
For the oxidation of lard and hexadecane in the series
of amines 1b—1d—1f and 1b—1h—1e—1g, the antiꢀ
oxidation activity decreased with a decrease in the numꢀ
ber of the orthoꢀtertꢀbutyl substituents and with their subꢀ
stitution for the methyl and cyclohexyl groups, i.e., with a
decrease in the degree of steric shielding of the phenolic
OH group. For the oxidation of hexadecane in the series
of hydroxybenzylamines 10a—d, a similar change in the
antioxidation activity was observed, depending on the
structure of substituents in the orthoꢀposition, whereas
benzylamine 10b with the "intermediate" methylꢀtertꢀbuꢀ
tyl orthoꢀsubstitution was most efficient for lard oxidation.
As a whole, the results of the present studies indicate
that in the series of the compounds synthesized the highꢀ
est total inhibitory activity belongs to N,Nꢀdimethylꢀalkylꢀ
ωꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyaryl)amines 1а—с,i, in
which the nitrogen atom is separated from the aromatic
N,NꢀDimethylꢀ5ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)pentylꢀ
amine (1i). 1ꢀChloroꢀ5ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)penꢀ
tane (2.3 g, 7.4 mmol), dimethylamine (2.0 g, 14.8 mmol), and
potassium carbonate (2.1 g, 14.8 mmol) were placed in a 50ꢀmL
ampule, and ethanol (10 mL) was added. The ampule was sealed,
placed in a thermostat with a shaking device, and stored for 7 h
at 120 °С. After cooling, the ampule was opened, and the reacꢀ
tion mixture was treated with an aqueous solution of NaOH and
then toluene. The extract was washed with water and dried over
Na2SO4, and the solvent was distilled off. The residue was disꢀ
tilled in vacuo, and amine 1i (1.8 g, 76%) was obtained, b.p.
148—150 °С (1 Torr), m.p. 91—92 °C (from hexane). Found (%):
С, 79.07; Н, 11.89; N, 4.14. C21Н37NО. Calculated (%):
С, 78.94; Н, 11.67; N, 4.38. 1Н NMR, δ: 1.36 (m, 2 H,
Аr(СН2)2СН2); 1.42 (s, 18 H, Вut); 1.50 (m, 2 Н Ar(СН2)3СН2);
1.60 (m, 2 H, АrСН2СН2); 2.20 (s, 6 H, NМе2); 2.25 (t, 2 H,
СН2N, J = 7.5 Hz); 2.50 (t, 2 H, АrСН2, J = 7.5 Hz); 5.01 (s,
1 H, ОН); 6.96 (s, 2 H, Ar).
Compounds 1e,h, 2d,e, and 3a,c,d were synthesized simiꢀ
larly from the corresponding haloalkanes.
N,NꢀDimethylꢀ3ꢀ(4ꢀhydroxyꢀ3,5ꢀdimethylphenyl)propylꢀ
amine (1e). The yield was 72%, b.p. 125—127 °C (1 Torr), m.p.
53.5—54 °C (from hexane). Found (%): С, 75.46; H, 10.40;
N, 6.48. С13Н21NО. Calculated (%): С, 75.31; Н, 10.21; N, 6.76.
1H NMR, δ: 1.68—1.75 (m, 2 H, АrСН2СН2); 2.20 (s, 6 H,
ArМе); 2.10 (s, 6 H, NМе2); 2.27 (t, 2 H, СН2N, J = 7.5 Hz);
2.47 (t, 2 H, АrСН2, J = 7.5 Hz); 5.43 (s, 1 H, ОН); 6.76
(s, 2 H, Ar).
N,NꢀDimethylꢀ3ꢀ(5ꢀtertꢀbutylꢀ4ꢀhydroxyꢀ3ꢀmethylpheꢀ
nyl)propylamine (1h). The yield was 72%, b.p. 129—131 °C
(1 Torr), m.p. 79—80 °C (from hexane). Found (%): С, 77.22;
H, 11.05; N, 5.48. С16Н27NО. Calculated (%): С, 77.06;
H, 10.91; N, 5.62. 1Н NMR, δ: 1.39 (s, 9 H, Вut); 1.69—1.76
(m, 2 H, АrСН2СН2); 2.19 (s, 3 H, ArМе); 2.22 (s, 6 H, NМе2);
2.28 (t, 2 H, СН2N, J = 7.5 Hz); 2.50 (t, 2 H, АrСН2, J =
7.5 Hz); 5.00 (s, 1 H, ОН); 6.80 (d, 1 H, Ar, J = 1.5 Hz); 6.93
(d, 1 H, Ar, J = 2.5 Hz).
N,NꢀDiethylꢀ3ꢀ(3ꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)propylamine
(2d). The yield was 90%, b.p. 145—147 °C (2 Torr). Found (%):
С, 77.74; Н, 11.25; N, 5.00. C17Н29NО. Calculated (%):
С, 77.51; Н, 11.10; N, 5.32. 1H NMR, δ: 1.04 (t, 6 H,

Inhibitory activity of alkyl(hydroxyaryl)amines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1153
N(СН2СН3)2, J = 7.5 Hz); 1.45 (s, 9 H, Вut); 1.80 (m, 2 H,
АrСН2СН2); 2.49 (t, 2 H, СН2NEt2, J = 7.5 Hz); 2.53 (t, 2 H,
АrСН2, J = 7.5 Hz); 2.64 (q, 4 H, N(СН2СН3)2); 6.00 (br.s,
1 H, ОН); 6.48 (d, 1 H, Ar, J = 8 Hz); 6.78 (dd, 1 H, Ar, J =
8 Hz, J = 2 Hz); 7.01 (d, 1 H, Ar, J = 2 Hz).
N,NꢀDiethylꢀ3ꢀ(4ꢀhydroxyꢀ3,5ꢀdimethylphenyl)propylamine
(2e). The yield was 90%, b.p. 145—147 °C (1 Torr). Found (%):
С, 76.78; Н, 10.94; N, 5.64. С15Н25NО. Calculated (%):
С, 76.55; Н, 10.71; N, 5.95. 1H NMR, δ: 0.96 (t, 6 H,
N(СН2СН3)2, J = 7.5 Hz); 1.65—1.72 (m, 2 H, АrСН2СН2);
2.20 (s, 6 H, Ме); 2.42—2.47 (m, 4 H, АrСН2СН2CН2);
2.51—2.55 (q, 4 H, N(СН2СН3)2); 4.80 (s, 1 H, ОН); 6.76
(s, 2 H, Ar).
N,NꢀDipropylꢀ2ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)ethylꢀ
amine (3а). The yield was 83%, b.p. 148—150 °C (2 Torr).
Found (%): C, 79.41; H, 11.85; N, 3.96. C22H39NO. Calcuꢀ
lated (%): С, 79.22; Н, 11.79; N, 4.20. 1H NMR, δ: 0.92 (t, 6 H,
N(CH2CH2CH3)2, J = 7.5 Hz); 1.49 (s, 18 H, Вut); 1.51 (m,
4 H, N(CH2CH2CH3)2); 2.45 (t, 4 H, N(CH2CH2CH3)2, J =
7.5 Hz); 2.65 (m, 4 H, ArCH2CH2); 4.94 (s, 1 H, OH); 6.94
(s, 2 H, Ar).
N,NꢀDipropylꢀ4ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)butylꢀ
amine (3c). The yield was 73%, b.p. 165—166 °C (1 Torr).
Found (%): C, 79.94; H, 12.04; N, 3.55. C24H43NO. Calcuꢀ
lated (%): С, 79.72; Н, 11.99; N, 3.87. 1H NMR, δ: 0.90 (t,
70—71 °C (from hexane). Found (%): С, 78.44; Н, 11.49;
N, 4.64. С19Н33NO. Calculated (%): С, 78.29; Н, 11.41; N, 4.81.
1H NMR, δ: 1.44 (s, 18 H, Вut); 1.60 (m, 4 H, АrСН2СН2СН2);
2.43 (s, 3 H, Me); 2.55 (t, 2 H, СН2NHMe, J = 7.5 Hz); 2.62 (t,
2 H, АrСН2, J = 7.5 Hz); 3.00—6.00 (br.s, 2 H, OH, NH); 6.97
(s, 2 H, Ar).
NꢀPropylꢀ2ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)ethylamine
(5а). The yield was 65%, b.p. 136—138 °C (1 Torr), m.p. 33 °C
(from hexane). Found (%): С, 78.48; Н, 11.57; N, 4.54.
С
19Н33NО. Calculated (%): С, 78.29; Н, 11.41; N, 4.81.
1H NMR, δ: 0.70—0.80 (br.s, 1 H, NH); 0.89 (t, 3 H,
NCH2CH2CH3, J = 7.5 Hz); 1.45 (s, 18 H, Вut); 1.43—1.51 (m,
2 H, NCH2CH2CH3); 2.56 (t, 2 H, NCH2CH2CH3, J = 7.5 Hz);
2.64 (t, 2 H, ArCH2CH2N, J = 7.5 Hz); 2.77 (t, 2 H, ArCH2,
J = 7.5 Hz); 4.92 (s, 1 H, OH); 6.89 (s, 2 H, Ar).
NꢀPropylꢀ3ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)propylamine
(5b). The yield was 68%, m.p. 66 °C (from hexane). Found (%):
C, 78.88; H, 11.61; N, 4.44. C20H35NO. Calculated (%):
1
С, 78.63; Н, 11.55; N, 4.59. H NMR, δ: 0.65—0.80 (br.s, 1 H,
NH); 0.91 (t, 3 H, NCH2CH2CH3, J = 7.5 Hz); 1.43 (s, 18 H,
Вut); 1.46—1.49 (m, 2 H, NCH2CH2CH3); 1.72—1.75 (m, 2 H,
АrCH2CH2); 2.50—2.55 (m, 4 H, CH2NCH2); 2.60 (t, 2 H,
ArCH2, J = 7.5 Hz); 4.90 (s, 1 H, OH); 6.87 (s, 2 H, Ar).
NꢀPropylꢀ4ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)butylamine
(5c). The yield was 64%, b.p. 156—158 °C (1 Torr), m.p. 41 °C
(from hexane). Found (%): C, 79.15; H, 11.73; N, 4.41.
C21H37NO. Calculated (%): С, 78.94; Н, 11.67; N, 4.38.
1H NMR, δ: 0.65—0.80 (br.s, 1 H, NH); 0.91 (s, 3 H,
NCH2CH2CH3); 1.43 (s, 18 H, Вut); 1.47—1.48 (m, 4 H,
АrCH2(CH2)2); 1.50—1.51 (m, 2 H, NCH2CH2CH3); 2.49 (t,
2 H, ArCH2, J = 7.5 Hz); 2.55 (t, 2 H, NCH2CH2CH3, J =
7.5 Hz); 2.61 (t, 2 H, CH2NHPr, J = 7.5 Hz); 4.85 (br.s, 1 H,
OH); 6.86 (s, 2 H, Ar).
2ꢀ(3,5ꢀDiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)ethylphthalimide (9a).
A mixture of 1ꢀbromoꢀ2ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxypheꢀ
nyl)ethane (10.1 g, 32.23 mmol), potassium phthalimide (7.2 g,
38.68 mmol), and DMF (50 mL) was heated for 6 h at 120 °C,
cooled, and filtered. The filtrate was treated with toluene, the
extract was washed with water and dried over Na2SO4, the solꢀ
vent was distilled off, and the residue was recrystallized from
ethanol. Alkylphthalimide 9а was obtained (9.0 g, 63%),
m.p. 130—132 °C. Found (%): С, 76.05; Н, 7.90; N, 3.47.
С24Н29NO3. Calculated (%): С, 75.96; Н, 7.70; N, 3.69.
1H NMR, δ: 1.38 (s, 18 H, Вut); 2.90 (t, 2 H, ArCH2, J =
7.5 Hz); 3.89 (t, 2 H, CH2N, J = 7.5 Hz); 5.06 (s, 1 H, OH);
6.99 (s, 2 H, Ar); 7.68, 7.81 (both m, 2 H each, Ar).
4ꢀ(3,5ꢀDiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)butylphthalimide (9с)
was synthesized similarly to phthalimide 9а. The yield was 68%,
m.p. 140—142 °C (from ethanol). Found (%): С, 76.81; Н, 8.23;
N, 3.25. С26Н33NO3. Calculated (%): С, 76.62; Н, 8.16; N, 3.44.
1H NMR, δ: 1.47 (s, 18 H, Вut); 1.69 (m, 2 H, ArCH2CH2);
1.79 (m, 2 H, Ar(CH2)2CH2); 2.60 (t, 2 H, ArCH2, J = 7.5 Hz);
3.77 (t, 2 H, CH2N, J = 7.5 Hz); 5.07 (s, 1 H, OH); 7.01 (s, 2 H,
Ar); 7.74, 7.88 (both m, 2 H each, Ar).
2ꢀ(3,5ꢀDiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)ethylamine (6a). Alkylꢀ
phthalimide 9a (3.0 g, 7.91 mmol) was dissolved in ethanol on
heating, and an aqueous solution of hydrazine hydrate (3.5 mL,
79.1 mmol) was added. The mixture was refluxed for 2 h and
then cooled, a solution of HCl (10 mL, 0.12 mol) was added,
and the resulting mixture was stirred for 0.5 h. Then water
(50 mL) was added, and the mixture was heated, stirred for 0.5 h
6
H, N(CH2CH2CH3)2, J = 7.5 Hz); 1.43 (m, 4 H,
N(CH2CH2CH3)2); 1.46 (s, 18 H, Вut); 1.49 (m, 2 H,
Ar(CH2)2CH2); 1.60 (m, 2 H, ArCH2СН2); 2.35 (t, 4 H,
N(CH2Et)2, J = 7.5 Hz); 2.42 (t, 2 H, CH2NPr2, J = 7.5 Hz);
2.53 (t, 2 H, ArCH2, J = 7.5 Hz); 4.89 (s, 1 H, OH); 6.89
(s, 2 H, Ar).
N,NꢀDipropylꢀ3ꢀ(3ꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)propylamine
(3d). The yield was 62%, b.p. 152—153 °C (1 Torr), m.p.
74—75 °C (from hexane). Found (%): C, 78.31; H, 11.59;
N, 4.67. C19H33NO. Calculated (%): С, 78.29; Н, 11.41; N, 4.81.
1H NMR, δ: 0.88 (t, 6 H, N(CH2CH2CH3)2, J = 7.5 Hz); 1.39
(s, 9 H, Вut); 1.46 (m, 4 H, N(CH2CH2CH3)2); 1.73 (m, 2 H,
ArCH2СН2); 2.38 (t, 4 H, N(CH2Et)2, J = 7.5 Hz); 2.44 (t, 2 H,
СН2N, J = 7.5 Hz); 2.49 (t, 2 H, ArCH2, J = 7.5 Hz); 6.04 (br.s,
1 H, OH); 6.39 (d, 1 H, Ar, J = 8 Hz); 6.78 (dd, 1 H, Ar, J =
8 Hz, J = 2 Hz); 7.01 (d, 1 H, Ar, J = 2 Hz).
NꢀMethylꢀ2ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)ethylamine
(4а). 1ꢀChloroꢀ2ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)ethane
(5.0 g, 18.6 mmol), methylamine (14.8 mL, 0.11 mol), and
potassium carbonate (5.1 g, 37.2 mmol) were placed in a 50ꢀmL
ampule, and ethanol (10 mL) was added. The ampule was sealed,
placed in a thermostat with a shaking device, and stored for 7 h
at 120 °C. After cooling the ampule was opened, and the reacꢀ
tion mixture was treated with an aqueous solution of NaOH and
then toluene. The extract was washed with water and dried over
Na2SO4, and the solvent was distilled off. The residue was disꢀ
tilled in vacuo, and target amine 4а was obtained (2.9 g, 60%),
b.p. 140—142 °C (1 Torr), m.p. 65—68 °C (from hexane).
Found (%): С, 77.38; Н, 10.97; N, 5.45. С17Н29NO. Calcuꢀ
lated (%): С, 77.51; Н, 11.10; N, 5.32. 1H NMR, δ: 1.42 (s,
18 H, Вut); 2.45 (s, 3 Н, Me); 2.73 (t, 2 H, ArCH2, J = 7.5 Hz);
2.82 (t, 2 H, CH2N, J = 7.5 Hz); 3.03—6.62 (br.s, 2 H, OH,
NH); 6.99 (s, 2 H, Ar).
Compounds 4c and 5a—c were synthesized similarly.
NꢀMethylꢀ4ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)butylamine
(4с). The yield was 72%, b.p. 169—172 °C (1 Torr), m.p.

1154
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Dyubchenko et al.
at 80 °C, cooled, and filtered. The filtrate was treated with an
aqueous solution of NaOH and then toluene. The extract was
washed with water and dried with Na2SO4, the solvent was disꢀ
tilled off, and the residue was recrystallized from hexane.
Amine 6а (1.3 g, 68%) was obtained, m.p. 108—110 °C
(from hexane) (cf. Ref. 22: m.p. 107.0—107.6 °C). Found (%):
С, 77.22; Н, 11.08; N, 3.47. С16Н27NO. Calculated (%):
С, 77.06; Н, 10.91; N, 3.69. 1H NMR, δ: 1.00—1.25 (br.s, 2 H,
NH2); 1.43 (s, 18 H, Вut); 2.66 (t, 2 H, ArCH2, J = 7.5 Hz); 2.93
(t, 2 H, СН2N, J = 7.5 Hz); 4.05—5.81 (br.s, 1 H, ОН); 6.98
(s, 2 H, Ar).
the obtained data. Using these kinetic curves, the induction
period was determined as the intersection point of two tangents
to the kinetic curve corresponding to the initial and final rates of
hexadecane oxidation.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 00ꢀ03ꢀ
32721); the STN International databases were accessible
through the STN Novosibirsk Center at the Novosibirsk
Institute of Organic Chemistry, Siberian Branch of the
Russian Academy of Sciences.
4ꢀ(3,5ꢀDiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)butylamine (6c) was
synthesized similarly to amine 6a from alkylphthalimide 9с. The
yield was 92%, m.p. 71—72 °C (from hexane) (cf. Ref. 22: m.p.
71—72 °C). Found (%): С, 78.01; Н, 11.45; N, 4.77. С18Н31NO.
References
1
Calculated (%): С, 77.92; Н, 11.26; N, 5.05. H NMR, δ: 1.42
(s, 18 H, Вut); 1.42—1.60 (br.s, 2 H, NH2); 1.48 (m, 2 H,
ArCH2CH2); 1.60 (m, 2 H, Ar(CH2)2CH2); 2.48 (t, 2 H, ArCH2,
J = 7.5 Hz); 2.69 (t, 2 H, СH2NH2, J = 7.5 Hz); 3.35—6.30
(br.s, 1 H, ОН); 6.89 (s, 2 H, Ar).
1. US Pat. 2003040594; Chem. Abstrs, 2003, 138, 189241.
2. US Pat. 2003031507; Chem. Abstrs, 2003, 138, 305086.
3. US Pat. 5814695; Chem. Abstrs, 1998, 129, 162267.
4. US Pat. 4863999; Chem. Abstrs, 1989, 112, 159707.
5. EP Pat. 474403; Chem. Abstrs, 1991, 116, 248431.
6. EP Pat. 500336; Chem. Abstrs, 1992, 117, 239832.
7. N. P. Konovalova, G. N. Bogdanov, L. S. Vasil´eva, L. M.
Dronova, and A. A. Matveeva, Dokl. Akad. Nauk SSSR,
1966, 168, 1419 [Dokl. Chem., 1966 (Engl. Transl.)].
8. E. B. Burlakova and N. G. Khrapova, in Teoriya i praktika
zhidkofaznogo okisleniya [Theory and Practice of LiquidꢀPhase
Oxidation], Ed. N. M. Emanuel, Nauka, Moscow, 1974, 244
(in Russian).
9. S. B. Bilalov, M. M. Movsumzade, and F. D. Alieva,
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10. F. Yu. Rachinskii, G. F. Bol´shakov, Yu. A. Bruk, M. Z.
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soderzhashchikhsya v neftyakh i nefteproduktakh [Chemistry
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1964, Vol. 7, 47 (in Russian).
In the kinetic studies, commercial ionol (Аcros Organics),
TMP (Lancaster), TBMP (Аcros Organics), and MP (Russia)
were used. 2,6ꢀDicyclohexylꢀ4ꢀmethylphenol was synthesized
using a known procedure.23
The k values were determined in model reactions of the
AIBNꢀinitiated oxidation of cumene and methyl oleate (all Acros
Organics) in chlorobenzene at 60 °C. Methyl oleate was purified
prior to use by double vacuum distillation.
The kinetics of oxygen absorption was studied using a highꢀ
sensitive capillary volumeter and a gasometric setup described
previously.15 The induction period (τ) was determined in the
plot as an intersection point of two tangents to the kinetic curve.
The slope ratios of these tangents were 0.5 and 0.75 of the slope
ratio of the straight line corresponding to the noninhibited reꢀ
action.15
The initiation rate (Wi) was determined by the inhibitor
method from the time of the end of the induction period of
cumene (methyl oleate) oxidation in the presence of ionol
or TMP
11. O. I. Dyubchenko, V. V. Nikulina, E. I. Terakh,
A. E. Prosenko, and I. A. Grigor´ev, Zh. Prikl. Khim.,
2005, 78, 796 [Russ. J. Appl. Chem., 2005, 78, 781 (Engl.
Transl.)].
12. O. I. Dyubchenko, V. V. Nikulina, E. I. Terakh, N. V.
Kandalintseva, A. F. Markov, I. A. Grigor´ev, and A. E.
Prosenko, Neftekhimiya, 2005, 45, 359 [Petroleum Chemisꢀ
try, 2005, 45, 330 (Engl. Transl.)].
Wi = 2[ArOH]0/τ,
where [ArOH]0 is the initial concentration of the inhibitor.
The main experiments on cumene oxidation were carꢀ
ried out at Wi = (0.2—1.4)•10–7 mol L–1 s–1 and [ArOH] =
(2.5—3.3)•10–5 mol L–1, and those on methyl oleate oxidation
were carried out at Wi = 1•10–7 mol L–1 s–1 and [ArOH] =
(2.0—4.0)•10–4 mol L–1
.
The oxidation of lard (produced at the Novosibirsk Meatꢀ
Packing Industrial Complex) was performed according to a deꢀ
scribed24 procedure using oxygen bubbling at 130 °C. The weight
of the oxidized sample was 50 g, and the concentration of the
inhibitors was 1.5 mmol g–1. During experiment 1ꢀg samples
were taken, and the concentration of the peroxide compounds
were determined by the iodometric method.25 The time, during
which lard was oxidized to the peroxide number 0.1, was used as
the induction period.
Hexadecane was oxidized at 180 °C in a gasometric setup
similar to that described earlier15 at an oxygen pressure of 1 atm.
The total volume of the sample was 5 mL and [ArOH] =
8.0 mmol L–1. The kinetic curves were plotted on the basis of
13. G. A. Kovtun and A. L. Aleksandrov, Izv. Akad. Nauk SSSR,
Ser. Khim., 1974, 1274 [Bull. Acad. Sci. USSR, Div. Chem.
Sci., 1974, 23 (Engl. Transl.)].
14. V. A. Roginskii, Fenol´nye antioksidanty: reaktsionnaya
sposobnost´ i effektivnost´ [Phenol Antioxidants: Reactivity
and Efficiency], Nauka, Moscow, 1988, 247 pp. (in
Russian).W
15. V. F. Tsepalov, in Issledovanie sinteticheskikh i prirodnykh
antioksidantov in vivo i in vitro [Investigation of Synthetic and
Natural Antioxidants in vivo and in vitro], Ed. E. B. Burlakova,
Nauka, Moscow, 1992, 16 (in Russian).
16. G. D. Kadochnikova, in Svobodnoradikal´noe okislenie
lipidov v eksperimente i klinike [Free Radical Oxidation

Inhibitory activity of alkyl(hydroxyaryl)amines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1155
of Lipids in Experiment and Clinic], Ed. V. N. Ushkalova,
Izd. Tyumen Gos. Univ., Tyumen, 1997, 21 (in Russian).
17. V. A. Roginskii, Kinet. Katal., 1990, 31, 546 [Kinet. Catal.,
1990, 31, 475 (Engl. Transl.)].
18. RF Pat. 1376511; Chem. Abstrs, 1993, 124, 316743.
19. RF Pat. 1370952; Chem. Abstrs, 1993, 125, 10363.
20. A. E. Prosenko, O. I. Dyubchenko, and A. P. Krysin, Tez.
dokl. region. konf. "Perspektivy razvitiya malotonnazhnoi
khimii" [Proc. Regional Conf. "Challenges of LowꢀTonnage
Chemistry], Krasnoyarsk, 1989, 22 (in Russian).
22. I. S. Belostotskaya and V. V. Ershov, Izv. Akad. Nauk SSSR,
Ser. Khim., 1964, 765 [Bull. Acad. Sci. USSR, Div. Chem.
Sci., 1964, 13, 715 (Engl. Transl.)].
23. Ya. B. Kozlikovskii, V. A. Koshchii, S. A. Butov, and A. V.
Sokolova, Zh. Org. Khim., 1987, 23, 1918 [J. Org. Chem.
USSR, 1987, 23 (Engl. Transl.)].
24. N. M. Emanuel and Yu. N. Lyasovskaya, Tormozhenie
protsessov okisleniya zhirov [Inhibition of Fat Oxidation],
Pishchepromizdat, Moscow, 1961, 385 pp. (in Russian).
25. A. A. Zinov´ev, Khimiya zhirov [Chemistry of Fats],
Pishchepromizdat, Moscow, 1952, 372 pp. (in Russian).
21. O. I. Dyubchenko, V. V. Nikulina, A. F. Markov, N. V.
Kandalintseva, A. E. Prosenko, O. M. Khoshchenko, Ya. Sh.
Shvarts, and M. I. Dushkin, Khim.ꢀFarm. Zh., 2006, 40, 117
[Pharm. Chem. J., 2006, 40 (Engl. Transl.)].
Received February 9, 2007;
in revised form May 15, 2007