Thermolysis of 4-(ω-hydroxyalkyl)-2,6-di-tert-butylphenols

Article abstract of DOI:10.1134/S1070363210020167

The process of thermolysis of tert-butylated hydroxyalkyl phenols includes de-tert-butylation, etherification, and fragmentation of the hydroxyalkyl group. On the basis of the proposed schemes of the mechanism of thermal de-tert-butylation the path of the search for catalysts for the synthesis of 4-hydroxyalkylphenols is defined and transformations of the by-products into biologically active substances were considered.

Full text of DOI:10.1134/S1070363210020167

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 2, pp. 275–283. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.P. Krysin, T.G. Egorova, V.G. Vasil’ev, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 2, pp. 250–258.
Thermolysis of 4-(ω-Hydroxyalkyl)-2,6-di-tert-butylphenols
A. P. Krysin, T. G. Egorova, and V. G. Vasil’ev
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences,
ul. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
e-mail: benzol@nioch.nsc.ru
Received July 2, 2009
Abstract―The process of thermolysis of tert-butylated hydroxyalkyl phenols includes de-tert-butylation,
etherification, and fragmentation of the hydroxyalkyl group. On the basis of the proposed schemes of the mechanism
of thermal de-tert-butylation the path of the search for catalysts for the synthesis of 4-hydroxyalkylphenols is defined
and transformations of the by-products into biologically active substances were considered.
DOI: 10.1134/S1070363210020167
It is known that all the variety of sterically hindered
phenols containing in aliphatic chain of the para-
substituent a functional group can be synthesized from
2,6-di-tert-butyl-4-(ω-hydroxyalkyl)phenols.
general, defines the technological advantage of the
thermolysis in comparison with the acid-catalyzed de-
tert-butylaton resulting as a rule in the isomerization of
the products and oligomerization of the formed
isobutylene [10].
Accessibility of the latter makes this approach
reasonable and offers a full range of substances for the
systematic research in a wide group of phenolic
compounds [1]. An example is the synthesis of phenols
containing sulfur in the aliphatic chain of the para-
substituent on different distances from the phenolic
fragment that is used in theory and in practice of the
search for effective and non-toxic termostabilizers for
polyolefins [2]. Based on the tert-butylated phenols (I–
III) by their de-tert-butylation systematic series of
phenol derivatives with pronounced biological activity
can be obtained [3].
Previously, by thermolysis of tert-butylated
hydroxyalkylphenols (I–III) we obtained a systematic
series of 4-(ω-hydroxyalkyl)phenols (V–VII) and their
mono-tert-butyl derivatives (VIII–X) [11]. Among
this group compounds in 4-(2-hydroxyethyl) phenol
(V), p-thyrozol, the most diverse biological activity is
detected. This compound can be defined as a
promising tool for the prevention and treatment of a
number of socially dangerous diseases [12]. Preventive
administration of p-thyrozol allows to increase
attention and memory, to reduce the tendency in
drivers to falling asleep at the wheel, to reduce the
time of responses at the selecting the right decision in
extraordinary situations that reduces the trauma of
people on the road. Its use is promising also in
agriculture to increase the productivity of poultry and
livestock [13]. Other compounds of this group, 4-(3-
hydroxypropyl) phenol (VI), is known as a means for
preventing the side effects of antibiotics and antitumor
drugs [14]. By physiological action it is related to the
group of phenylpropanoids [15].
The first data on the thermal de-tert-butylation of
2,6-di-tert-butylphenol derivatives we obtained by the
example of selective formation of 2-tert-butylphenol
from 2,6-di-tert-butylphenol (IV) that is impossible to
carry out under acid catalysis: the catalytic methods
led to formation mainly of 2,4-di-tert-butylphenol [4].
Further studies have shown that by thermolysis some
new biologically active compounds can be obtained,
derivatives of ortho-tert-butylphenol and para-sub-
stituted phenols containing in the aliphatic chain of the
para-substituent chlorine, bromine, as well as
hydroxy-, amino-, methoxy- or carboxy group [5–9]
Thermal processes of their preparation proceed in the
absence of a catalyst and without the generation of iste
water. This is a chemistry without a solvent that, in
The thermolysis of tert-butylylated hydroxyalkyl-
phenols (I–III) results in the hydroxyalkylphenols (V–
VII) of a high degree of purity [11], but the process
itself because of large quantities of iste and moderate
yield of p-thyrozol requires careful investigation and
275

276
KRYSIN et al.
improvement. At present the mechanism of thermo-
lysis is not clear, and there is no information for the
creation of selective catalysts, which significantly
complicates the problem.
seem doubtful. We believe that the possible explana-
tion of this process is the initial formation of the
corresponding tozylate followed by its thermal de-tert-
butylation. Without a clear understanding of the
essence of acid-catalyzed and thermal de-tert-butyla-
tion of arenes it is impossible to expect further pro-
gress in this practically important direction of
chemistry.
Proceeding from the similarity in the composition
of the main products of de-tert-butylation of 4-methyl-
2,6-di-tert-butylphenol by thermal [8] and by acid-
catalyzed methods [3], on the basis of the data
obtained it is possible to suggest that these two
processes are identical. However, if we use 2,6-di-tert-
butylphenol, as well as more complex structures of
tert-butylated phenols containing a functional group in
the aliphatic chain of the para-substituent, a significant
difference in the nature of the products is observed.
Thermolysis of compounds I over 7–8 h in a flow
of nitrogen at 285°C proceeds with the evolution of
isobutylene and leads to 4-(2-hydroxyethyl)-2-tert-
butylphenol (VIII) [11].
In the present work we identified new processes
occurring at the subsequent heating of the compound
in the temperature range 285–295°C. We revealed the
composition of volatile fraction (3%) formed during
the thermolysis of compound I. It contains equal
quantities of phenol, methyl-, ethyl-, and butylphenols.
This indicates partial or complete fragmentation of
hydroxyalkyl substituent in the process of formation of
these phenols. The basic process is a full de-tert-
butylation of compound I with the formation of p-
thyrozol. In the process of its synthesis along with p-
thyrozol from the reaction mixture by vacuum
distillation a high-boiling fraction (bp 240–270°C at
4 mm Hg) is isolated in 21% yield and still bottoms
The acid-catalyzed de-tert-butylation of compound
I acetate derivative at the aliphatic hydroxy group, in
the presence of a heteropolyacid and aromatic hydro-
carbon proceeds with the formation of derivatives of
dibenzyl [16]. Heating of compound I at 210°C for
1 h in the presence of trace quantity of p-
toluenesulfonic acid leads to a product of crosslinking
of the initially formed mono-tert-butylated compound
VIII [11]. In the light of these transformations, the
data in the patent [17] concerning the process of de-
tert-butylation of compound I in the presence of excess
toluenesulfonic acid and diethylbenzene at 220°C
OH
OH
OH
(CH2)n
+ HO
O
+
2
(CH2)nOH
(CH2)nOH
(CH2)nOH
VIII−X
I−III
XI, XII
(CH2)n
V−VII
O
+
+ HO
HO
(CH2)nO
(CH2)nOH
2
XIII
XIV
Fraction with bp to
200oC
O
+
OH
R1
O
+
+
+
C24H26O4,
C32H34O5
HO
HO
XVI
XVII
R2
n: 2 (I, V, VIII, XI, XIII, XIV), 3 (II, VI, IX), 4 (III, VII, X, XII); R1 = R2 = H; R1 = t-Bu, R2 = H;R1 = H, R2 = CH3; R1 =
H, R2 = C2H5.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 2 2010

277
THERMOLYSIS OF 4-(ω-HYDROXYALKYL)-2,6-DI-tert-BUTYLPHENOLS
(14%). Formation of these products, as shown below,
is determined by the processes of de-tert-butylation
and etherification.
The studied fraction also contains in small quantity
two isomeric tert-butylated ethers XI, XVIII with
MW = 314.19 (peaks RT = 19.8' and 19.95'). They
contain one more tert-butyl group than ethers XIII–
XV. By HPLC method we determined the presence in
a small quantity of products XVI and XVII. In
accordance with their molecular masses and UV
spectra (λmax = 310 nm) these compounds presumably
have the structure of hydroxybenzofuran XVI (RT =
17.7') and its tert-butylated derivatives XVII (RT =
19.65').
The results of HPLC–MS analysis of the high-
boiling faction are listed in the table.
To the basic component corresponds a peak with
RT = 17.25'. Judging from the molecular weight
257.12, UV spectrum, and empirical formula of this
substance, this is ether XIV. It is isolated in an
individual form and its structure is studied by NMR
spectroscopy.
The still bottoms after distillation consisted of a
mixture of isomeric p-thyrozol tri- and tetramers with a
large predominance of the latter.
In addition to ether XIV, in the investigated
fractions two isomeric ethers XIII and XV were
detected, which have similar UV spectra (corres-
ponding to the peaks with RT 17.3' and 17.44'). Ether
XIII could be identified after isolation of enriched
fraction, but we failed to elucidate the structure of
ether XV.
By the example of the thermolysis of 4-(4-
hydroxybutyl-2,6-di-tert-butyl)phenol (III) we found
that in this case the formation of diethers also occurs.
This allowed to suggests that the formation of ethers as
HPLC–MS analysis of composition of high-boiling fraction after thermolysis of 4-(2-hydroxyethyl)-2,6-di-tert-butylohenol
(I)
Retention time,
min
Phenoxide anion
Positive ions, m/z and
Maxima in UV spectra, Compound no.
Peak area, %
17
(М – Н+), m/z
(intensity, %)
nm
and formula
15.30
257.12
121.07 (30)
147.08 (30)
165.09 (8)
241.12 (100)
278.11 (20)
278.61 (7)
407.17 (12)
407.67 (6)
121.07 (100)
278.11 (57)
278.61 (20)
121.07 (100)
241.12 (23)
278.11 (20)
278.61 (7)
180.06 (37)
149.10 (28)
311.17
278
XIII
(C16H18O3)
17.25
17.44
55
20
257.12
257.12
276
276
XIV
(C16H18O3)
XV
(C16H18O3)
17.70
19.65
19.80
2
2
2
253.09
309.15
313.18
310
311
278
XVI
(C16H14O3)
XVII
(C20H22O3)
XI
121.07 (50)
177.13 (100)
337.18 (50)
121.07 (38)
177.13 (100)
337.18 (43)
(C20H26O3)
19.95
2
313.18
278
XVIII
(C20H26O3)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 2 2010

278
KRYSIN et al.
by-products is a characteristic direction of the
thermolysis of tert-butylated hydroxyalkylphenols.
The basic process is consecutive splitting off two tert-
butyl groups of the parent molecule (III), resulting in
its final phase in 4-(4-hydroxybutyl)phenol (X) in
about 60% yield [11].
mediate products for the synthesis of biologically
active substances.
We showed that the formed mixture of diethers
XIII–XIV and still bottoms (p-thyrozol tri- and
tetramers) under the action of excess hydroiodic acid
gave in a good yield 4-(2-iodoethyl)phenol (XIX). Its
properties as a low toxic iodine-containing agent are
currently under study. The transformation of iodide
XIX into the p-thyrozol X is described in [18].
A technological challenge is to find the ways of
transformation of the formed side ethers XIII–XIV
and still bottoms into p-thyrozol or in other inter-
OH
HI
(C H O ) + (C H O ) + XIII, XIV
+
24 26
4
32 34 5
(CH2)2I
XIX
HBr
(1) AcONa
(2) NaOH
CH3ONa
20oC
HO
(CH2)2Br
HO
(CH2)2OCH3
V
XX
XXI
Heating of diether XIV, as well as a mixture of
ethers XIII–XIV with hydrobromic acid led to 4-(2-
bromoethyl)phenol (XX) in a moderate yield. At the
dissolution of this compound in a methanol solution of
sodium methoxide 4-(2-methoxyethyl)phenol (XXI) is
formed, a key product in the synthesis of methaprolol
[7]. Earlier we reported on the transformation of p-
thyrozol into bromide XX, and then into thyramine [6].
Thermal de-tert-butylation of 4-(3-hydroxypropyl)-
and 4-(4-hydroxybutyl)-2,6-di-tert-butylphenols (II,
III) is carried out in a flow of inert gas at a
temperature 290°C for 8 h with the formation of o-tert-
butylphenol derivatives IX, X; further heating leads to
the corresponding 4-hydroxyalkylphenols VI, VII in
60–80% yield [11].
We observed that the products of thermal
transformation of compounds I–III contain no side
products formed at the acid-catalyzed reaction. The
formation of pure isobutylene at the thermal de-tert-
butylation of these phenols should be also added. The
formation of pure isobutylene at the thermolysis of
tert-butylphenol has been noted as an unusual
phenomenon and patented [22], since the same process
in the presence of acid is accompanied by the
formation of isobutylene dimer and oligomers.
Occasional introduction of even trace quantities of acid
to the reactor where the process of thermolysis of
compound I is performed (which is possible at
sampling) leads to a rapid tarring of the reaction
mixture.
Bromide XX is transformed into p-thyrozol in a
one-pot two-stage chemical process. By boiling it with
aqueous solution of sodium acetate a mixture of p-
thyrozol and the respective acetate (at the alcohol
group) in a ratio of 1:3 is formed. Subsequent alkaline
hydrolysis of the mixture affords crude p-thyrozol in
95% yield. Crystallization of the product gives the p-
thyrozol with the content of the substance 99.7%. The
necessity to obtain p-thyrozol of a high degree of
purity is noted in literature [19], and it is connected
with its application in the form of injection at the
treatment of cardiovascular disease occurring in acute
myocardial infarction or in stroke [20, 21].
Note that the high purity of substabce V attained by
us is defined first of all by the high selectivity of the
process of thermal de-tert-butylation of phenols, not
leading to the formation of difficultly separated
isomers.
It is known that under the action of irradiation of
the methyl ether derived from compound I occurs a
partial fragmentation of its hydroxyethyl fragment with
the formation of benzyl radical and formaldehyde. The
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 2 2010

279
THERMOLYSIS OF 4-(ω-HYDROXYALKYL)-2,6-DI-tert-BUTYLPHENOLS
scheme of formation of these species with the
involvement of radical-cations has been proved [23]. It
is not excluded that in our case the observed at the
thermolysis of compounds I partial and complete
fragmentation of its hydroxyethyl fragment and tert-
butyl group may have a common explanation and the
essence of this transformation is the occurrence of the
radical processes.
strength of Ar–OH (D0) for the derivatives of 2,6-di-
tert-butylphenol is in the range of 82±3 kcal mol–1. For
unsubstituted phenols it is noticeably higher: 86±
2 kcal mol–1 [25]. Comparison of these data suggest
that the de-tert-butylating by thermolysis of ortho-tert-
butylphenol is rather unusual reaction in which the
goal is achieved owing to the initial energetic excita-
tion of the neighboring hydroxy group.
Investigation of the kinetics of the thermolysis of
tert-butylated phenols [9, 24] allows to recognize the
structural factors affecting the strength of Ar–C(CH3)3
bond which by the data of [29] is 91.3 kcal mol–1. The
Basing on the above data, we present our under-
standing of the thermolysis of tert-butylphenol, using a
simplified hypothetical scheme of trans-formation of
compound IV into 2-tert-butylphenol and isobutylene.
CH2
OH
OH
O
290oC
IV
OH
IV
−
O
OH
CH
C
+
2
It includes the formation from 2,6-di-tert-
butylphenol by thermal pathway of phenoxide radical,
interaction of the latter with the tert-butyl fragment, a
stage of formation of isobutylene and tert-
butylphenoxide radical. Interaction of the latter with
the parent 2,6-di-tert-butylphenol molecule induces a
new circle of transformations. The key stage of this
scheme is the process of thermal ionization of the
sterically hindred phenol with the formation of
phenoxide radical , which requires a high energy [25].
The latter can explain the fact why the thermal de-tert-
butylation of compounds I–III at a temperature of
300°C proceeds slowly. The high reactivity of
phenoxide radicals that they display at a temperature of
130°C and higher is well known: they react with
alkanes with the regeneration of the parent phenol [25,
26]. In our case, the role of the alkanes may play the
tert-butyl group of starting compound IV. It is known
that the reaction of phenoxide radicals with substrates
leads to intermediate formation of phenoxide anion
and cation-radical of the substrate [27] and the
doubtless involvement of these active particles in the
considered process should also be taken into
consideration.
Related cyclic processes may probably proceed also
with the phenoxide anions. The step of abstraction by
the phenoxide anion of hydrogen atom from the tert-
butyl group we studied by the method of deuterium
exchange [28]. The second phase, the removal of
isobutylene, may lead to the formation of anion
containing a negative charge on the aromatic ring. Its
interaction with the initial 2,6-di-tert-butylphenol gives
2,6-di-tert-butylphenoxide anion, which repeats the
cycle of transformations leading eventually to the
foromation of 2-tert-butylphenol as the final product.
In these schemes the common point is the use of the
energy of the phenol hydroxy group in the thermal
processes leading to the removal of the neighboring
tert-butyl group.
The above considerations indicating the necessity
of the prior activation of hydroxy group of tert-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 2 2010

280
KRYSIN et al.
butylphenol may be used in the search for a catalyst for
the thermal de-tert-butylation. We found that the
composition of the reactor material affects the course
of thermal process and can accelerate it. Thus, the
presence in a glass reactor of the crushed Klin glass
(the glass of Russian production containing a
maximum percentage of alkali metals is chosen) in the
process of thermolysis of compounds I leads to an
increase in thyrozol yield from 61 to 72%. It can be
assumed that the interaction of tert-butylphenol with
the alkali metals on the glass surface under the action
of high temperature can lead to formation of alkali
metal phenoxides, whose thermal decomposition, as
follows from the value of dissociation energy D0 =
60±4 for the Na–O bond [29], requires much less
energy in comparison with Ar–OH bond in the parent
tert-butylphenols (D0 = 82±3). These data can be used
as a basis for the search for more efficient catalysts for
the thermal de-tert-butylation of compounds I–III.
Synthesis of p-thyrozol III by thermolysis. Example
1. Into the glass receiver of fractionation column of
1 l capacity with thermometer and an inlet for an inert
gas was placed 694 g (2.69 mol) of 97% freshly
distilled 4-(2-hydroxyethyl)-2,6-di-tert-butylphenol (I). The
reaction mixture was heated at a temperature 295–298°C
for 22 hours, at passing through the liquid a flow of
nirogen. The temperature of heated rectification column
was 185°C. During this time from the reactor was
distilled off 10 g of a labile liquid containing,
according to the GLC, equal quantities of phenol,
4-methylphenol, 4-ethylphenol, and butylphenol.
The residue was distilled in a vacuum, the first
fraction collected, 231.5 g, bp 195°C (11 mm Hg),
contained 98% of thyrozol (according to GLC). The 1H
NMR spectrum of III in CD3OD, δ, ppm: 2.74 t, J =
7 Hz, Ar–CH2–, 2H; 3.71 t, J = 7 Hz, –CH2OH, 2H;
6.73, J = 9 Hz; 7.06 d, J = 9 Hz; system AA'BB',
4H. After crystallization from a mixture of ethanol–
chloroform we obtained 205 g of 99.7% purity thyro-
zol with mp 92–93ºC in the form of transparent
needles. Yield 55%.
EXPERIMENTAL
The system for HPLC-MS analysis consisted of
liquid chromatograph Agilent 1200 (with a diode-
matrix detector) and a hybrid quadrupole–time-on-fly
mass spectrometer micrOTOF-Q (Bruker). Column:
Zorbax XDB-C8, 2.1×150 mm, particle size
3.5 micron. Eluent: 2% HCOOH–MeOH, linear gradient
from 30 to 90% of methanol since 5th to 15th min. Flow
rate: 0.2 ml min–1. UV detection is carried out at three
wavelengths: 255/16, 280/16 and 320/32 nm. Besides,
each second of the available to the system UV spectra
(50 spectra per minute) in the range 230–450 nm is
saved.
The second faction, 80 g (21%), viscous oil, bp
240–270 °C (4 mm Hg). According to HPLC–MS
analysis (see the table), it consisted to 96% of three
ethers XIII–XV in the ratio 1: 3.2: 1.2. At long
standing the oil hardens, the crystals were collected
and crystallized from CCl4. 40 g of di-[2-(4-hyd-
roxyphenyl)]ethyl ether (XIV) was obtained as white
powder, mp 85–87ºC (from CCl4 with addition of
methyl-tert-butyl ether). Found: M+ 258.1258 (mass
spectrometry). Calculated: M+ = 258.1256, C16H18O3. UV
spectrum in ethanol, λmax, nm, (log ε): 202 (4.215) 225
(4.069), 278 (3.440). 1H NMR spectrum of compound
VIII in CD3OD, δ, ppm: 2.68 t, J = 6 Hz, Ar–CH2–,
4H; 3.50 t, J = 6 Hz, –CH2O–, 4H; 6.74 d J = 9 Hz,
6.98 d, J = 9 Hz, system AA'BB', ArH, 8H; 8,83 s, –
Working parameters of mass-detection. Ionization
method: Electrostatic spraying at atmospheric pressure
(API-ES). Scanning of negative ions in the range m/z =
100–900. The drying gas flow (nitrogen) rate: 8 l min–1,
its temperature: 230°C, pressure in the sprayers:
1.6 bar.
13
OH, 2H. The C NMR spectrum in CD3OD, δC, ppm:
36.11 (C7), 73.07 (C8), 116.04 (C2,6), 130.75 (C3,5),
131.05 (C4), 156.31 (C1).
1-[4-(2-Hydroxyethyl)phenoxy]-2-(4'-hydroxyphe-
nyl)ethane (XIII). Oil. Found: M+: 258.12626 (mass
spectrometry). Calculated: M 258.12559. C16H18O3. The
1H NMR spectrum of compound XIII in CD3OD, δ,
ppm: 2.76 t, J = 6 Hz, Ar–CH2–, 2H; 2.93 t, J = 6 Hz,
Ar–CH2–, 2H; 3.70 t, J = 6 Hz, –CH2O–, 2H; 4.06 t,
J = 6 Hz,–CH2OAr, 2H; 6.7–7.12 m, Ar–H, 8H.
Chromato-mass spectrometric analysis of phenols is
carried out on a Hewlett-Packard device, which
includes a gas chromatograph HP 5890 series II and a
mass-selective detector HP 5971. Capillary column
HP5MS 30 m × 0.25 × 0.25 μm. Carrier gas helium.
The H and 13C NMR spectra were recorded on a
Bruker AV-300 instrument (300.13 MHz) from 10%
solutions in CD3OD. Melting temperature is deter-
mined with the Köfler unit.
1
The still bottoms after distillation (40 g) was a
fragile black mass. According to mass spectrometry, it
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 2 2010

281
THERMOLYSIS OF 4-(ω-HYDROXYALKYL)-2,6-DI-tert-BUTYLPHENOLS
contained compounds with m/z 378.165 (C24H26O4) and
m/z 498.244 (C32H34O5), corresponding to p-thyrozol
trimer and tetramer, respectively. The average mole-
cular weight of the still bottoms determined by
ebullioscopy was 485, which indicates a predominance
of the thyrozol tetramer.
was distilled off. The residual solution was acidified
with hydrochloric acid and extracted with ether. The
organic layer wass washed with water, and the solvent
was distilled off. 15 g ether XXI was obtained of
90% purity, which was purified by distillation in a
vacuum, the fraction of bp 131–135 °C (3 mm Hg) was
collected giving 12
g
(yield 79%) of 4-(2-
Example 2. To a flask of 70 ml volume with
Vigreux column and a gas inlet tube was placed 26
of crushed glass of Klin plant production and 33 g
(0.13 mol) of 99% compound I, and the mixture was
heated at 290±5°C in a flow of argon for 19 h. The
reaction mixture was dissolved in boiling toluene, the
resulting solution was decanted from viscous black
residue, cooled to 0°C, the precipitate was filtered.
13.3 g of thyrozol was obtained (yield 72%) with 97%
content of the basic substance according to the GLC.
methoxyethyl)phenol (XXI), mp 35–38 °C. According
to [7] mp of compounds XXI is 41–43 °C (from
toluene).
4-(3-Hydroxypropyl)phenol (VI). Into a steel
reactor was loaded 5.8 kg of 97% purity 4-(3-
hydroxypropyl)-2,6-di-tert-butylphenol (II) and 2 l (by
total volume) of Rashig rings (hollow glass cylinders
10×15 mm). The reaction of de-tert-butylation was
carrued out at passing nitrogen from the bottom of the
steel reactor. The temperature in the reactor was
slowly raised from 280 to 300ºC (in total 24 h). Dark
oil, 2.8 kg, was obtained which contained according to
the GLC 73% of 4-(3-hydroxypropyl)phenol (VI) and
18% of 4-(3-hydroxypropyl)-2-tert-butylphenol (IX). At
the distillation in a vacuum a fraction of bp 150–160ºC
(2 mm Hg) was collected, which crystallized from
chloroform. Yield 1.8 kg (57%) of compound VI of
98% purity, mp 52–54ºC (mp 49–50ºC according to
[30]).
Example 3. Synthesis of p-thyrozol from bromide
(XX). To a flask with reflux condenser was placed
8.05 g (0.04 mol) of 4-(2-bromoethyl)phenol XX,
40 ml of water, and 6 g of sodium acetate. The mixture
was boiled for 3 h. After that to the boiling reaction
mixture in a flow of inert gas was added gradually 2 g
of NaOH dissolved in water and the boiling was
continued for another 30 min. Then water was distilled
off in amount of 2/3 of the volume and the residue was
cooled to room temperature. The residue was acidified
to pH = 3 and extracted with ether. The ether layer was
separated, washed with water, and the solvent was
distilled off. 6 g of an oil, a solution of thyrozol in
acetic acid, was obtained. The acid is neutralized by
saturated aqueous solution of NaHCO3. Solid
precipitate was separated by fitration, washed with
water, and dried. Thyrozol, 5.0 g, was obtained,
mp 91–92°C, contents of the basic substance
98%. Yield 88%.
The still bottoms was dissolved in ether, washed
with 5% aqueous solution of NaOH and water. Then
the solvent was distilled off and the residue was
distilled in a vacuum, providing 0.4 kg of fraction of
bp 160–175ºC (2 mm Hg) containing 4-(3-hyd-
roxypropyl)-2-tert-butylphenol (IX) of 96% purity.
Yield 9%. This product was stored at room tem-
perature as an oil. Its spectral characteristics coincide
with those of the product IX, obtained earlier by the
same method [4, 11, 31].
Dimerization of compound I by heating in the
presence of acid. In a glass reactor, 3 g of 4-(2-
hydroxyethyl)-2,6-di-tert-butylphenol (I) was heated
in the presence of 10 mg of p-toluenesulfonic acid at a
temperature of 210°C for 1 h. According to GLC, the
reaction mass contained 40% of starting compound I,
10% of 2-tert-butyl-4-(2-hydroxyethyl) phenol (VII),
and 50% of the dimerization product of compound VII
with a molecular weight M = 370.53 (mass spectrum),
corresponding to C34H24O3,
Synthesis of 4-(2-iodoethyl)phenol (XIX) from
ether XIV. To a flask with a stirrer and a reflux
condenser was placed 4 ml of 57% hydroiodic acid and
0.56 g (0.0022 mol) of ether XIV. The reaction
mixture was heated in a bath at a temperature of 150ºC
with stirring for 3 h, then poured on ice, filtered, and
washed with CCl4. 1.0 g (0.004 mol) of white crystals
was isolated, yield 91%, mp 111–112ºC (from
1
CCl4). According to [9] mp 110–112ºC. H NMR
spectrum of solution of compounds XIX in CCl4, δ,
ppm: 3.05 t, J = 7 Hz, Ar–CH2–, 2H; 3.22 t, J = 7 Hz,
–CH2I–; 6.65 d, J = 9 Hz, H–Ar, 2H; 6.97 d, J = 9 Hz,
H–Ar, 2H.
Synthesis of 4-(2-methoxyethyl)phenol (XXI). A
solution of 20.1 g (0.1 mol) of 4-(2-bromethyl) phenol
XX in 160 ml of 10% solution of NaOCH3 in methanol
was kept at room temperature for 3 h, then methanol
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 2 2010

282
KRYSIN et al.
Synthesis of iodide (19) from still bottoms. 24.2 g
6.5 g (77%) of compound X, bp 175–177ºC (3 mm
of still bottoms containing 20% of trimer and 80% of
tetramer of p-thyrozol (average molecular weight 485)
was heated in a reactor with 60 g of 57% hydroiodic
acid at 150ºC with stirring for 4 h. After cooling the
reaction mixture, the acid layer was separated and the
residue was extracted with ether, ether layer was
washed with water. After evaporation of the solvent
the product was distilled in a vacuum, fraction 135–
142ºC (2 mm Hg) was collected. Compound XIX,
of 95% purity, 17 g, was obtained. Yield 36%.
Hg), was isolated and 0.8 g of a fraction of di-4-(2-
tert-butyl-4-hydroxyphenyl)butyl
ether
(XXII),
bp 270ºC (2 mm Hg) in the form of viscous oil.
Found: m/z
=
424.2979 (mass spectrometry).
C28H40O3. Calculated: m/z = 424.2977.
4-(4-Hydroxybutyl)-2-tert-butylphenol (X).
Oil. Found: m/z = 222.1615. C14H22O2. Calculated:
m/z = 222.1614. The 1H NMR spectrum (in CD3OD) δ,
ppm: 1.40 s, C(CH3)3, 1.5–1.7 m CH2CH2–, 2.54 t J =
7 Hz, ArCH2–, 3.56 t, J = 7 Hz, –CH2OH; 4.93 s, OH;
6.65 d, J = 8.5 Hz, 1H, 6.85 d.d, J' = 8,5 Hz, J" = 2 Hz,
1H; 7.02 d, J"= 2 Hz, 1H.
Synthesis of 4-(2-bromoethyl)phenol (XX) from
ether XIV. In a reactor with a stirrer and a column for
distilling off water 12 g of compound XIV and 20 ml
of concentrated hydrobromic acid was heated for
6 h. After cooling, the acid layer was separated, and
the residue was dissolved in methyl-tert-butyl ether.
Ether layer was washed with water, ether was
evaporated, and residue was distilled in a vacuum, a
fraction of bp 138–140ºC (3 mm Hg) was collected.
Compound XX, 8.7 g, was isolated, yield 51%, mp
4-(4-Hydroxybutyl)phenol (VII), mp 53–
55ºC. Found: m/z = 166.1001. C10H14O2. Calculated:
1
m/z = 166.0994. The H NMR spectrum (in CD3OD),
δ, ppm:1.5–1 .7 m, –CH2CH2–; 2.54 t, J = 7 Hz,
ArCH2 –; 3.64 t, J = 7 Hz,–CH2OH; 5.64 s, OH; 6.73
d, J = 8.5 Hz, 6.99 d, J = 8.5 Hz (system AA'BB'),
Ar–H (4H).
1
88–89ºC (from trichlorethylene). The H NMR spec-
REFERENCES
trum (in CCl4), δ, ppm: 3.01 t, J = 7 Hz, Ar–CH2–;
3.41 t, J = 7 Hz, –CH2I; 6.66 d, J = 8.5 Hz, 6.98 d, J =
8.5 Hz, AA'BB' system, H–Ar, 4H.
1. Ershov, V.V., Nikiforov, G.A., and Volod’kin, A.A.,
Prostranstvenno-zatrudnennye
fenoly
(Sterically
Hindred Phenols), Moscow: Khimiya, 1972.
Synthsis of bromide XX from a mixture of
ethers XIII–XV. To a reactor with stirrer and an
adapter for separation of water and volatile
components formed during the reaction was placed
12 g of a mixture of ethers XIII–XV and 20 ml of
concentrated hydrobromic acid. The reaction mixture
at stirring was heated to gentle boiling for 6 h and
dilute HBr and tert-butyl bromide were distilled
off (bp of distillate 103ºC). The boiling temperature
grew therewith to 124ºC. After cooling, the reaction
mixture was separated by decanting acid layer, and the
solid residue was dissolved in methyl-tert-
butyl ether. The ether layer was washed with water,
ether was distilled off, and the residue was distilled in
a vacuum. 4-(2-Bromethyl)phenol (XX), 8.7 g (yield
51%) bp 138–140ºC (3 mm Hg), mp 88–89ºC (from
trichlorethylene) was obtained.
Thermolysis of 4-(4-hydroxybutyl)-2,6-di-tert-
butylphenol (III). In a glass reactor 11 g (0.038 mol)
of 97% compound III was heated at 290–295ºC in a
flow of argon for 8 h. Oil, 8.6 g, was obtained
containing by the data of GLC 3% of the parent
compound III, 4% of 4-(4-hydroxybutyl)phenol (VII),
85% of 4-(4-hydroxybutyl)-2-tert-butylphenol (X), and
few other compounds. By distillation in a vacuum
2. Lugova, L.I., Makarova, G.P., Tsvetkova, A.I.,
Sotnikova, L.K., Dudinova, L.N., and Lazareva, N.P.,
Sbornik nauchnykh trudov ONPO Plastpolimer. Sintez,
svoistva, pererabotka poliolefinov (Collection of
Scientific Publications of Industrial Division
Plastpolymer. Synthesis, Properties, and Processing of
Polyolefins), Leningrad: 1984, pp. 152–158.
3. Kulikov, S.M., Krysin, A.P., Titova, T.F., Timofee-
va, M.N., and Kozhevnikov, I.V., Author’s Certificate
SSSR no. 1609067, 1987, Byull. Izobret., 1999, no. 24.
4. Krysin, A.P., Kun, O.B., Kuzubova, L.I., and
Ostashevskaya, L.A. Author’s Certificate SSSR
no. 1085970, 1983, Byull. Izobret., 1984, no. 14.
5. Prosenko, A.E., Kim, A.M., Krysin, A.P., and Kop-
tyug, V.A., Author’s Certificate SSSR no. 1162781,
1985, Byull. Izobret., 1985, no. 23.
6. Krysin, A.P., Egorova, T.G., Prosenko, A.E., and
Kobrin, V.S., RF Patent no. 2218326, 2003, Byull.
Izobret., 2003, no. 34.
7. Krysin, A.P., Vasilevskaya, T.N., Knyazev, V.V.,
Egorova, T.G., Akhmetova, N.E., and Yakovleva, O.M.,
RF Patent no. 2100341, 1996, Byull. Izobret., 1997,
no. 36.
8. Kun, O.B., Nogina, N.I., Ostashevskaya, L.A., Ego-
rov, E.M., Kuzubova, L.I., and Krysin, A.P., Zh. Org.
Khim., 1984, vol. 20, no. 12, pp. 2609–2611.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 2 2010

283
THERMOLYSIS OF 4-(ω-HYDROXYALKYL)-2,6-DI-tert-BUTYLPHENOLS
9. Pilati, F., Masoni, S., and Berti, C., Polym. Commun.,
Tolstikov, G.A., and Tolstikova, T.G., RF Patent
no. 2239423, 2003, Byull. Izobret., 2004, no. 34.
1985. vol. 26, no. 9, pp. 280–282.
10. Saleh, S.A. and Tashtoush, H.I., Tetrahedron., 1998.
21. Que Wendin, Chone Patent no. 1.569.196, 2005, C.A.,
vol. 54, pp. 14157–14177.
2006, vol. 144, no. 57377.
11. Krysin, A.P., Egorova, T.G., and Kobrin, V.S., RF
22. Dawson, O.H., USA Patent no. 2 366 497, 1945,
Patent no. 2063395, 1994, Byull. Izobret., 1996, no. 19.
C.A.,1945, vol. 39, no. P18812 .
12. Saratikov, A.S. and Krasnov, E.A., Rodiola rozovaya,
zolotoi koren’ (Rodiole rose, Gold Root), Tomsk,
Tomsk Univ., 2004.
23. Bociocchi, E., Bietti, M., Manduchi, L., and Steen-
ken, S., J. Am Chem. Soc., 1999, vol. 211, no. 18,
pp. 6624–6629.
13. Shkil’, N.A., Prudnikov, S.I., Yushkov, Yu.G.,
Tolstikov, G.A., Egorova, T.G., Kobrin, V.S., Kry-
sin, A.P., RF Patent no. 2181587, 2002, Byull. Izobret.,
2002, no. 12.
14. Hayashi, K., Watanabe, A., Shimane, Y., Shimane, Y.,
Kuwayama, M., Fujioka, T., Uchida, C., and Naka-
shima, T., Japan Patent no. 81 115 716A, 1981, C.A.,
1982, vol. 96, no. 62975p.
15. Kurkin, V.A., Dubishchev, A.V., Titova, I.N., Volo-
tsueva, A.V., Petrova, E.S., Zhestkova, N.V., and
Klimova, I.Yu., Rastitel’nye Resursy, 2003, no. 3,
pp. 115–121.
24. Nikulicheva, O.N., Krysin, A.P., and Fadeeva, V.P., Zh.
Prikl. Khim., 2008, vol. 81, no.9, p.1517–1522
25. Roginskii, V.A., Fenol’nye antioksidanty. Reaktsi-
onnaya sposobnost’
i
effektivnost’ (Phenolic
Antioxidants. Reactivity and Efficience), Moscow:
Nauka, 1988, pp. 28–30, 124–125.
26. Neiman, M.B., Mamedova, Yu.G., Blenke, P., and
Buchachenko, A.L., Dokl. Akad. Nauk SSSR, 1962,
vol. 144, no. 2, pp. 392–396
27. Malmaström, J., Jonsson, M., Cotgreaave, I.A.,
Hammarström, L., Sjödin, M., and Engman, L., J. Am.
Chem. Soc., 2001, vol. 123, pp. 3434–3440.
16. Titova, T.F. and Krysin, A.P., Zh. Org. Khim., vol. 30,
28. Krysin, A.P., Pokrovskii, L.M, and Shakirov, M.M., Zh.
no.10, pp. 1513–1516.
Org. Khim., 2000, vol. 36, no.1, pp.79–86.
17. Wada, I., Japan Patent no. 2000–19213A, 2000, C.A.,
29. Energiya razryva khimicheskikh svyazei. Potentsialy
ionizatsii i srodstvo k elektronu (Energy of Breaking
Chemical Bonds. Ionization Potentials and Electron
Affinity), Kondrat’ev, V.N., Ed., Mosow: Nauka, 1974.
2000, vol. 133, no. 350048.
18. Borkowski, B., Kołodynska, S., Lada, E., and
Wieniawski, W., Acta Polon. Pharm., 1997, vol. 34,
no. 3, pp. 221–225.
30. Novitskii, V.F., Izv. Akad. Nauk Bel. SSR, Ser. Khim.,
19. Araki, Y., Kumamoto, N., and Banno, T., Japan Patent
1972, no. 3, pp. 97–100.
no. 02218632A, 1990, C.A., 1991, vol. 114, no. 101344.
31. Prosenko, A.E., Skorobogatov, A.A., Dyubchenko, O.I.,
Pinko, P.I., Kondalintseva, N.V., Shakirov, M.M., and
Pokrovskii, L.M., Izv. Russ. Akad. Nauk, Ser. Khim.,
2007, no. 6, pp. 1078–1083.
20. Plotnikov, M.B., Maslov, M.Yu., Chernysheva, G.A.,
Smelyakova, V.I., Aliev, O.I., Vasil’ev, A.S., Kry-
sin, A.P., Sorokina, I.V., Salakhutdinov, N.F.,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 2 2010