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Selective Monoetherification of 1,4-Hydroquinone Promoted by NaNO2


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Catalytic amounts of NaNO2 are able to successfully promote the reaction between 1,4-hydroquinone and methanol under acidic conditions, affording selectively the corresponding mequinol in excellent isolated yields. According to the proposed reaction mechanism, the semi-quinone intermediate, generated in situ from the corresponding hydroquinone by NO2 oxidation, is the real reactive species, undergoing nucleophilic attack onto the alcoholic molecule. Experimental evidences emphasize the key role of NO2. After optimization of the reaction conditions, the scope of the proposed protocol is extended to a wider range of alcohols, providing the corresponding mono-ethers in good to excellent yields. Moreover, when substituted hydroquinones are selected as reactive substrates, monoetherification occurs with complete regio-selectivity towards the less hindered phenolic OH group.
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1108 Current Organic Chemistry, 2013, 17, 1108-1113
Selective Monoetherification of 1,4-Hydroquinone Promoted by NaNO2
Cristian Gambarotti,* Lucio Melone, Carlo Punta and Suresh Udhavrao Shisodia
Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, via Mancinelli, 7 – 20131
Milano, Italy
Abstract: Catalytic amounts of NaNO2 are able to successfully promote the reaction between 1,4-hydroquinone and methanol under
acidic conditions, affording selectively the corresponding mequinol in excellent isolated yields. According to the proposed reaction
mechanism, the semi-quinone intermediate, generated in situ from the corresponding hydroquinone by NO2 oxidation, is the real reactive
species, undergoing nucleophilic attack onto the alcoholic molecule. Experimental evidences emphasize the key role of NO2. After opti-
mization of the reaction conditions, the scope of the proposed protocol is extended to a wider range of alcohols, providing the corre-
sponding mono-ethers in good to excellent yields. Moreover, when substituted hydroquinones are selected as reactive substrates, mono-
etherification occurs with complete regio-selectivity towards the less hindered phenolic –OH group.
Keywords: Etherification, Alkylation, Hydroquinones, Semiquinone.
Monoethers of 1,4-hydroquinone, and in particular mequinol
and monobenzone, are products of great interest from both an in-
dustrial and a biological point of view. The monomethyl ether of
1,4-hydroquinone, commonly named mequinol, is an important
building block which is also used as antioxidant for edible oils and
greases, polymerization inhibitor for acrylic compounds, stabilizer
for photo sensitive materials, lubricating additive for high-
temperature gas turbine engine oils, and key intermediated in many
pharmacological applications [1].
Historically, monoethers are prepared by means of the William-
son Reaction, which consists in the reaction of a halide with an
alkoxide or an aroxide [2]. Besides this approach, many synthetic
protocols have been developed, based on the selective monoetheri-
fication of hydroquinone derivatives.
In 1900, Russig reported the first conversion of naphthoqui-
nones into monoalkylated ethers of the corresponding naphthohy-
droquinones. The Russig-Laatsch procedure consists in the initial
reduction of quinone with sodium dithionite followed by reaction
with an alcohol saturated with HCl [3]. An alternative approach,
based on the use of dimethylsulfate in a two-phase system in the
presence of sodium hydroxide, allowed to obtain mequinol in up to
80 % yield [4].
More recently, ion-exchanged zeolites have been used to pro-
mote the selective O-methylation of hydroquinone by methanol [5].
In this protocol, the selectivity depends on the zeolite’s basicity and
on the operating temperature, which is generally maintained above
200 °C.
It was found that high selectivity towards mono-alkylation of
1,4-hydroquinone could be obtained in the presence of catalytic
quantities of p-benzoquinone. Following this simple approach,
many companies were able to develop processes for the production
of mequinol on industrial scale. In the 70th Kodak Eastman patented
*Address correspondence to this author at the Department of Chemistry, Materials and
Chemical Engineering "Giulio Natta", Politecnico di Milano, via Mancinelli, 720131
Milano, Italy; Tel: +39 0223994748; Fax: +39 02 23993180;
the direct mono-O-methylation of 1,4-hydroquinone by methanol in
the presence of catalytic amounts of sulfuric acid and p-
benzoquinone [6]. Hereafter, Enichem Synthesis developed a new
process in which the catalyst p-benzoquinone was produced in-situ
from hydroquinone in the presence of H2O2 [7]. Moreover, in 2005
Yadav et al. reported the use of various heteropolyacids supported
on montmorillonite to achieve mequinol from hydroquinone and
methanol [8]. Even if it appears evident that the presence of p-
benzoquinone is crucial in the above mentioned protocols in order
to afford the desired products in good yields, its role in the reaction
mechanism is still controversial. Yadav and co-workers [8] sug-
gested an ionic mechanism according to which protonated methanol
adds to a protonated benzoquinone chemisorbed on the heterogene-
ous catalyst. However, while this mechanism emphasizes the ad-
sorption role of the heterogeneous acidic catalyst, it does not ex-
plain the real function of benzoquinone under homogeneous condi-
tions. Furthermore, according to the proposed mechanism, it is not
clear why di-substitution does not occur. It is well known that 1,4-
hydroquinone (HQ) and p-benzoquinone (BQ) generate an equilib-
rium reaction in solution, affording two molecules of the corre-
sponding semiquinone intermediate (SQ) (Scheme 1) [9].
We suggest that the in situ generation of semiquinone could
play a key role in the reaction. On the basis of this mechanism in-
terpretation, we here report a new protocol for the selective
monoetherification of hydroquinone promoted by tiny amounts of
NaNO2 in acidic methanol (Scheme 2). The optimized conditions
are extended with success to a wider range of alcohols, proving the
scope of the reaction.
All starting materials were purchased from commercial suppli-
ers without further purification. All reactions were performed under
atmosphere of nitrogen. An Agilent 6890 Gas Cromatograph (GC)
system equipped with a 30mt x 0.250mm HP-5MS GC column and
an Agilent 5973 Mass Selective Detector (MSD) detector were used
to identify the reaction products. NMR spectra were recorded at 400
MHz for 1H and 100 MHz for 13C. 1H NOESY analyses were con-
ducted on a Bruker 500 MHz spectrometer, setting the mixing time
1875-5348/13 $58.00+.00 © 2013 Bentham Science Publishers
Selective Monoetherification of 1,4-Hydroquinone Promoted Current Organic Chemistry, 2013, Vol. 17, No. 10 1109
at 300 ms, temperature at 298 K, sweep width at 10 ppm and the
TD in F1 dimension at 512.
General procedure in the presence of NaNO2: Hydroquinone
(10 mmol), H2SO4 (98 %, 10 mmol) and NaNO2 (0.5 mmol), were
stirred in 20 ml of alcohol at room temperature and under N2 at-
mosphere for the times reported in Tables 1 and 2. The mixture was
poured in water (100 mL) and extracted with CHCl3 (100 mL x 3
times). The organic phase was dried with Na2SO4 and the solvent
evaporated under vacuum providing hydroquinone monoether 3
crystals. The crude product was further purified by flash chroma-
tography onto silica-gel (40-63 m) using hexane:ethyl acetate
(85:15 (v:v)) as eluent, affording 3 as the first eluted product (Rf =
0.35 on analytical TLC ).
Similar experiments were performed using solid acidic catalyst
(Amberlyst® A15 and Amberlite® IR120) in place of H2SO4, as
detailed in Tables 2 and 3.
Conversion and selectivity were determined by GC-MS analy-
sis by sampling 100L of the reaction mixture before the work-up,
adding 2,6-dimethyl-1,4-benzoquinone as internal standard and
diluting with CHCl3. Yields of isolated products are based on the
starting hydroquinones.
Monoalkyl ethers were identified by GC-MS and NMR spec-
troscopy by comparison with authentic samples.
General procedure in the presence of NO2: Hydroquinone
(10 mmol) and acidic catalyst (solid catalyst (2 g) or H2SO4 (98 %,
10 mmol) were added to 20 mL of methanol under N2 atmosphere
and the solution was maintained under magnetic stirring at the tem-
peratures reported in Tables 3. NO2was produced in a separate
three necked round bottom flask (purged with N2 before NO2 pro-
duction) by adding drop wise a solution of NaNO2 (7.2 mmol - 0.5
g, in 5 mL of water) in 5 mL of 50 % H2SO4 aqueous solution over
a time of 30 minutes. The produced red vapors were directly bub-
bled into the reaction mixture through a porous silica diffuser and
the mixture was allowed to react for the times reported in Table 3.
The mixture was filtered, if required to remove the solid catalyst,
poured in water (100 mL) and extracted with CHCl3 (100 mL x 3
times). Mequinol 3a and BQ were identified according to the pro-
cedures previously described.
In order to optimize the reaction conditions, we initially focused
our attention onto the monomethylation of hydroquinone 2a (HQ)
to mequinol 3a (MQ, Scheme 2 R = CH3) starting from methanol
1a as alkylating agent. The results are reported in Table 1.
When operating at room temperature, the H2SO4/NaNO2 system
led to a complete conversion in just 1 hour with 100 % selectivity in
mequinol (Table 1, entry 1) and no decomposition was observed
even after 24 hours, showing how, under these mild conditions, the
product is stable and the reaction is easily controllable. On the con-
trary, when the same reaction was conducted at reflux, tars were
Scheme 1. Formation of semiquinone from 1,4-hydroquinone and p-benzoquinone.
Scheme 2. Monoetherification of HQ catalyzed by NaNO2.
Table 1. Synthesis of mequinol from 1,4-hydroquinone and methanol in the presence of NaNO2 and H2SO4[a]
# Acid NaNO2 (mmol) T (°C) t (h) Conv. (%) Sel. (%)
1 H2SO4 (10 mmol) 0.5 r.T. 1 100 >99
2 H2SO4 (1 mmol) 0.5 r.T. 3 20 >99
3 H2SO4 (1 mmol) 0.5 r.T. 24 100 >99
4 - 0.5 r.T. 24 0 -
5 H2SO4 (10 mmol) - r.T. 24 0 -
6 H2SO4 (10 mmol) 0.5 reflux 1 100 < 30
7b H
2SO4 (10 mmol) - r.T 24 100 99
8b H
2SO4 (10 mmol) - reflux 4 100 96
9c H
2SO4 (100 mmol) 5 r.T. 1 100 >99
Experiments carried out under N2 athmosphere. [a] 10 mmol of hydroquinone in 20 mL of methanol at room temperature. [b] 0.5 mmol of benzoquinone were employed in place of
NaNO2. [c] 100 mmol of hydroquinone in 50mL of methanol at room temperature. Conversions and yields determined by GC-MS.
2+2 H+2
+R-OH +H2O
1110 Current Organic Chemistry, 2013, Vol. 17, No. 10 Gambarotti et al.
mostly recovered even after just 1 hour (Table 1, entry 6). The
amount of H2SO4 was chosen in order to maintain an equimolar
ratio between HQ and acid. By reducing the H2SO4 quantity up to
10 % with respect to HQ, the reaction run slower (Table 1, entry 2)
and a complete conversion was achieved only after 24 hours (Table
1, entry 3), while no products were recovered in the absence of acid
or NaNO2 (Table 1, entries 4 and 5).
Moreover, when the reaction was carried out using a higher
amount of HQ (100 mmol in place of 10 mmol) and a reduced vol-
ume of methanol (Table 1, entry 9), a complete conversion was
observed with a selectivity similar to that reported under diluted
conditions. This result shows the potential of this protocol, proving
how it can be reproduced on larger scales.
When BQ was employed in place of NaNO2at room tempera-
ture, the complete conversion was reached only after 24 hours,
while an increase of temperature up to reflux of methanol allowed
to achieve complete conversion and selectivity in just 4 hours
(Table 1, entry 7).
Commercially available Amberlyst 15 and Amberlite IR120
were also used as solid acidic catalysts (Table 2). Both consist in a
strongly acidic styrene-based sulfonated polymer bearing about 4.5
meq/g of –SO3H groups. As expected, the homogeneous reaction in
the presence of H2SO4 was faster than the reactions catalyzed by
solid acids (Table 2, entries 1, 6), whereas no products were recov-
ered in the absence of NaNO2 (Table 2 entries 3, 4, 8, 9).
The experiments catalyzed by H2SO4 in which BQ was used in
place of NaNO2 gave complete conversion and high selectivity after
longer reaction times (Table 1, entries 7, 8), whereas lower conver-
sions were observed in the presence of solid catalysts (Table 2,
entry 10).
In conclusion, by operating under milder conditions the
H2SO4/NaNO2 system showed a higher efficiency in terms of con-
version, selectivity, product stability and reaction time if compared
with the heterogeneous systems, the latter requiring longer reaction
times to afford, in any case, a lower selectivity.
The proposed mechanism involves the initial formation of
semiquinone radical (SQ) from the corresponding hydroquinone by
the oxidation in the presence of catalytic amounts of NaNO2. Ac-
cording to Scheme 3, under acidic conditions NaNO2 affords HNO2
in situ (Eq. 1); the latter rapidly decomposes forming NO2 (Eq. 2)
which in turn is able to efficiently oxidize HQ to SQ [10].Working
at room temperature, the decomposition of NaNO2to NO2 is
enough fast to efficiently promote the oxidation HQ to SQ, avoid-
ing, at the same time, further Michael substitution, which leads to
the formation of the corresponding 2,4-methoxy phenol (Scheme
4). This product was observed with BQ when operating in the pres-
ence of solid catalysts.
Scheme 3. Semiquinone generation promoted by NaNO2 under acidic con-
To confirm our hypothesis of mechanism, a set of experiments
were performed in which NO2 was used in place of NaNO2 (Table
3). In these cases, NO2 was produced in a separate round bottom
flask by decomposition of NaNO2 in acidic medium and directly
bubbled into the reaction mixture during its development. The ex-
periments were performed either using H2SO4 orA15 or IR120 as
acidic catalysts (Table 3). The decomposition of NaNO2 by H2SO4
was achieved by adding drop wise the solution of NaNO2 in a 50 %
H2SO4 solution, over a time of 30 minutes. The red NO2 vapors so
formed were directly bubbled into the reaction mixture through a
porous silica diffuser. During the bubbling period the reaction solu-
tion turned dark due to the formation of BQ. In all the experiments
3a was achieved as major product, this confirming the intervention
of NO2 in the reaction mechanism. Anyway lower conversions were
observed compared to the reactions performed in the presence of
NaNO2, probably due to the gas-liquid mass transfer resistance. In
Table 2. Synthesis of mequinol from 1,4-hydroquinone and methanol in the presence of NaNO2 and solid catalyst[a]
# Solid acid NaNO2 (mmol) T (°C) t (h) Conv. (%) Sel. (%)
1 A15 0.5 r.T. 24 100 90
2 A15 0.5 reflux 4 100 96
3 A15 - r.T. 24 0 -
4 A15 - reflux 4 0 -
5b A15 - reflux 4 50 93
6 IR120 0.5 r.T. 24 100 95
7 IR120 0.5 reflux 4 100 97
8 IR120 - r.T. 24 0 -
9 IR120 - reflux 4 0 -
10b IR120 - reflux 4 38 98
Experiments carried out under N2 athmosphere. [a] 10 mmol of hydroquinone and 2g of solid acidic catalyst in 20 mL of methanol. [b] 0.5 mmol of benzoquinone were employed in
place of NaNO2. Conversions and yields determined by GC-MS.
H+ cat.
Selective Monoetherification of 1,4-Hydroquinone Promoted Current Organic Chemistry, 2013, Vol. 17, No. 10 1111
the presence of H2SO4 the reaction was fast even at room tempera-
ture. Nevertheless, the selectivity was slightly lower than the reac-
tions in the presence of solid catalysts, and BQ was observed as by
product (Table 3, entry 1). In the presence of solid catalysts, BQ
was the main by-product (Table 3, entries 2), while low amounts of
Michael adduct (less than 2 %) were found in the reactions carried
out at reflux (Table 3, entries 3 and 4).
An experiment was also performed by reacting resorcinol (1,3-
dihydroxybenzene) in place of HQ under the same conditions of
experiment listed in Table 1, entry 1. Resorcinol should be not able
to form the corresponding semiquinone and, as expected, no prod-
ucts were recovered after 24h.
The SQ radical presents two important characteristics: the bond
dissociation energy for the O-H bond (54 kcal/mol is significantly
lower than that in the corresponding diphenol (81 kcal/mol) while
its acidity is extremely higher (pKa = 4.0) compared to that of HQ
(pKa = 9.9) [11]. The lower dissociation energy for the O-H bond in
semiquinone is explained by the conjugation of the unpaired elec-
tron with the aromatic ring (Scheme 5).
Scheme 5. Delocalization of unpaired electron of semiquinone.
The slightly high acidity of semiquinone is strictly connected
with its low dissociation enthalpy. The pkavalue of SQ radical,
analogous to that of acetic acid, suggests an occurring acid-base
equilibrium which leads to the formation of a radical-anion inter-
mediate under mild acidic or alkaline conditions (Scheme 6).
Scheme 6. Acid-base dissociation reaction of semiquinone.
As carboxylic acids, which are easily esterified by reaction with
alcohols in acidic medium, the radical adduct can also attack the
alcohol affording the mequinol radical species. The latter undergoes
hydrogen atom abstraction from a pristine hydroquinone leading to
the formation of the final desired product and a new SQ molecule,
which prolongs the radical chain (Scheme 7).
Scheme 7. Monoether formation mechanism.
In accordance with the proposed mechanism, further O-
alkylation of the remaining free OH group does not occur and no
traces of diethers are observed even after complete conversions, as
monoalkyl ether is less acidic than corresponding semiquinone
radical and is not able to reacts with alcohols.
Therefore, this protocol was successfully applied to several al-
cohols, as shown in Table 4. In the experiments with benzyl alcohol
and cyclohexanol, acetonitrile was used as co-solvent in order to
obtain an homogeneous solution.
In the presence of benzyl alcohol (Table 4, entry 4) an increase
of the reaction time led to higher conversions, but with a lower
selectivity due to the competitive formation of dibenzyl ether. In the
presence of tert-butanol (Table 4, entry 8) the low selectivity has to
be ascribed to the formation of high amounts of BQ as principal by-
product, while the reaction conducted with propargyl alcohol (Table
Scheme 4. 2,4-dimethoxy phenol formation mechanism.
Table 3. Synthesis of mequinol in the presence of NO2 and solid catalyst[a]
# Acid Catalyst T (°C) t (h) Conv. (%) Sel. (%)
1 H2SO4(10 mmol) r.T. 1 77 90
2 IR120 (2g) r.T. 24 45 96
3 IR120 (2g) Reflux 4 34 94
4 A15 (2g) Reflux 4 45 93
Experiments carried out under N2 athmosphere. [a] 10 mmol of hydroquinone and acid catalyst in 20 mL of methanol.; 0.5 g of NaNO2 in 5 mL of H2O drop wise added to 5 ml of
50% H2SO4. Conversions and yields determined by GC-MS.
1112 Current Organic Chemistry, 2013, Vol. 17, No. 10 Gambarotti et al.
4, entry 9) led to the formation of the desired product 3i in a moder-
ate yield despite a relevant amount of tars was observed.
The etherification of substituted hydroquinones like 2,3,5-
trimethyl- (Table 4, entry 10) and 2-methyl-1,4-hydroquinones
(Table 4, entry 11) was also investigated. In both cases a total
conversion was observed with good isolated yields of the desired
monoethers. Anyway, the selectivity was lower than the corre-
sponding un-substituted HQ mainly due to the formation of BQ and
over-oxidized by-products as evidenced by GC-MS analysis. In
spite of the asymmetry of the substrates, which would suggest the
formation of two possible isomers, in both cases the reaction led to
the formation of unique products with complete regio-selectivity.
The monoethers structures were identified by 2D 1H NOESY analy-
sis (see supplementary information). As evidenced by the correla-
tion between the methyl-ether and the two aromatic hydrogens in
the case of 2k and between the aromatic hydrogen and the near
methyl group in the case of 3j, both the etherifications underwent
onto the less hindered phenolic –OH.
Mono-ethers of hydroquinone are of particular interest both for
industrial and biological applications. The reaction of hydroquinone
with alcohols, in the presence of catalytic quantities of benzoqui-
none and acids, gives the corresponding monoethers with both high
yields and selectivities. The acidic behavior of the semiquinone
specie provides, in the reaction media, the nucleophilic semiqui-
none, which attack the alcohol affording the mono-O-alkylated
product. Higher selectivities toward the mono-O-alkylation are
observed when semiquinone is generated in-situ through oxidation
of hydroquinone by NaNO2, via intermediate formation of NO2. The
Table 4. Monoetherification of hydroquinone with different alcohols in the presence of NaNO2 and H2SO4.
# Alcohols Quinone T °C t (h) Conv.
(%) Sel.
(%) Products Isolated
Yield (%)
1 Methanol 1a
rt 1 100 >99
2a, [12] Ethanol 1b
rt 3 100 93
3 [13] 1-Butanol 1c
rt 72 95 >99
4b, [14] Benzyl alcohol 1d
rt 24 87 86
5 [15] iso-Propanol 1e
rt 24 95 >99
6 [16] Allyl alcohol 1f
rt 24 99 98
7b, [17] Cyclohexanol 1g
rt 48 90 >99
8tert-Butanol 1h
rt 48 48 63
9 Propargyl alcohol 1i
rt 3 100 45
10c Methanol 1a
rt 3 100 70
11c Methanol 1a
rt 3 100 87
Experiments carried out under N2 athmosphere. [a] 7 % of benzoquinone is formed; [b] 10 mL of CH3CN were added to increase solubility; [c] confirmed by 1H NMR NOESY
analysis. Conversions and selectivities determined by GC-MS.
Selective Monoetherification of 1,4-Hydroquinone Promoted Current Organic Chemistry, 2013, Vol. 17, No. 10 1113
reactions occur under mild conditions (room temperature and at-
mospheric pressure of nitrogen), preventing the formation of Mi-
chael by-products onto p-benzoquinone. The possibility to extend
the procedure on a wide range of alcohols and on substituted hy-
droquinones, together with the excellent results achieved by operat-
ing at 10 times larger scale, makes this protocol an intriguing alter-
native for the synthesis of mono-ethers of hydroquinones in high
yields and selectivity under very mild conditions.
The author(s) confirm that this article content has no conflict of
We thank MIUR for continual support of our free-radical chem-
istry (PRIN 2010-2011, project 2010PFLRJR_005). Special thanks
to Dr. Franca Castiglione of Politecnico di Milano for the important
help given in the acquisition and elaboration of 1H NOESY NMR
Supplementary material is available on the publishers Web site
along with the published article.
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Received: September 03, 2012 Revised: February 13, 2013 Accepted: February 13 2013
... [28] Mono and di O-methylated products of 1,4-hydroquinone, named 4-methoxyphenol and 1,4-dimethoxybenzene have an enormous attention from both an industrial and a biological point of view. [29] 4-methoxyphenol is an active ingredient in topical drugs used for skin depigmentation. [30] It also has wide applications such as an antioxidant, a polymerization inhibitor in vinyl and acrylic monomers, an intermediate in manufacturing of dyes and pharmaceuticals, a stabilizer of photosensitive materials and acrylic acid. ...
... Several papers and patents have been published on O-alkylation of phenol and hydroquinone with dimethyl carbonate and methanol as methylating agent in presence of different catalysts such as mineral acids, ionic liquids, ion exchange resins, zeolites, solid acid and basic catalysts, mixed metal oxides and hydrotalcites. [29,[35][36][37][38][39][40] The present work reviews the progress on alkylation of phenol and hydroquinone using several catalysts employing methanol and dimethyl carbonate as methylating agent. Influence of reaction parameters and active sites on catalyst surface on conversion of reactant and product selectivity is elaborated. ...
... The methylation of hydroquinone with methanol in presence of various heterogeneous catalysts such as alkali loaded silica and zeolites, alumina, ion exchange resins, acid loaded clays and mineral acids such as sulfuric acid, perchloric acid and hydrohalic acid has been explored experimentally. [9,29,33,136] Grote [137] claimed a continuous process for etherification of water soluble hydroquinone using methanol or dimethyl ether in a fixed bed reactor over silica and alumina as catalyst in temperature range of 505-645 K. Author reported maximum 70% yield of 4-methoxyphenol along with 1,4-dimethoxybenzene as byproduct. Etherification of phenolic compounds with methanol in presence of tertiary amines or corresponding salts at higher temperature was studied by McCloud et al. [8] and also the influence of different acid such as sulfuric acid, acetic acid and hydrochloric acid was examined on yield of hydroquinone mono and di-methyl ether and results for the same are summarized in Table 9. ...
The alkylation process involves two competitive paths of O- and C-alkylation and achieving better selectivity for desired products is a very challenging problem. The development of new process for synthesis of O-methylated products of phenol and dihydric phenols is a subject of high industrial and academic interest. Alkyl phenyl ethers, especially anisole and 4-methoxyphenol, have captivated significant interest due to their increasing applications in pharmaceutical industries. The main emphasis of the present review is to explore the recent development in two catalytic O-alkylation processes. The first process is O-methylation of phenol into anisole and another is selective mono O-methylation of hydroquinone into 4-methoxyphenol. The present article covers O-alkylation methods with methanol and dimethyl carbonate as alkylating agent over various acidic and basic catalytic systems. The catalyst systems analyzed involves Bronsted and Lewis acidic and basic ionic liquids, conventional acids, metal oxides, solid acid and basic catalysts, hydrotalcites, various zeolites and heteropolyacids. The mechanistic behavior of alkylation reactions in presence of different catalytic system is reviewed critically which is important to design new and/or modified catalyst in order to maximize the yield of desired product. Additionally, an influence of reaction parameters, role of catalyst and their active sites on product distribution is described. The review paper gives useful insight for researchers in the field of catalysis and reaction engineering of alkylation reactions. Understandings of the reaction pathways will help in developing reliable kinetic models necessary for process scale-up to industrial scale reactor system.
... It is challenging to get a single product selectively due to various competitive O-and C-alkylation reactions. Numerous methods for synthesizing the O-methylated product of HQ have been reported, involving the use of sulfuric acid, hydrohalic acid, perchloric acid, and acetic acid in the presence of triethylamine and their salts [1][2][3][4]. Various heterogeneous catalysts such as silica, alumina, zeolites, alkali-loaded silica and zeolite, ion exchange resins, acid loaded clays have been reported [5][6][7][8][9][10][11]. Recently, various functionalized Bronsted acidic ionic liquids have been reported for selective O-methylation of HQ [12,13]. ...
... The lone pair of oxygen atoms in BQ attacks the methyl group of MeOH that leads to the formation of I 4 and water(5). The reaction between HQ and I 4 involves the abstraction of hydride from HQ leading to BQ regeneration with intermediate I 5 , which on deprotonation result in a product, 4-MP (4).Figure 11indicates the reaction between intermediate I4 and MeOH, which involves the abstraction of hydride from MeOH representing the role of MeOH as a reducing agent. The intermediate I 5 on deprotonation results in 4-MP formation. ...
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An environmentally benign process for synthesizing 4-methoxyphenol through methylation of hydroquinone using polystyrene immobilized Bronsted acidic ionic liquid is presented. The catalyst has been characterized by several techniques, such as solid-state NMR, FTIR, and XRD. The morphological properties were analyzed through SEM and TEM analysis. The elemental analysis was performed using EDS and XPS techniques. The catalyst was thermally stable up to 603 K, which was confirmed by TGA. The chemical interaction between ionic liquid and polystyrene was confirmed by measuring the glass transition temperature of pure polystyrene and catalyst. The BET analysis was performed to estimate the catalyst’s surface area, pore size, and pore volume. The recyclability of the proposed new catalyst was established up to five recycle runs in the batch mode. In addition, continuous flow experiments were conducted to test the catalytic activity in terms of catalyst life span and showed excellent stability up to 20 h. The rapid separation, long-term stability, and efficient recycling of synthesized polymeric catalysts make an excellent alternative to the commonly used homogeneous catalysts for selective O-methylation of hydroquinone reaction. The newly developed continuous process for synthesizing 4-methoxyphenol with 100% selectivity suggests good opportunities to reduce energy consumption, which designates a cost-effective process. Graphical Abstract
... In a three-necked flask fitted with dropping funnel, refrigerant and magnetic stirrer, accurately flamed and under nitrogen stream, sulfuric acid (24 ml) and chitosan (0.6 g) were added. Then, hydroquinone (0.5 g) and sodium nitrite (0.0156 g) were added at room temperature and under magnetic stirring, and the reaction was maintened for 72 h [26]. After that there was the separation of the two phases, aqueous and organic, by means of a separating funnel. ...
... Briefly, the gauze was initially carboxylated and characterized. The quantitative analysis of the carboxy groups [26], has revealed a content of 0.469-50 mg of gauze. The FT-IR spectrum showed the presence of a new band at 1725 cm −1 due to the acid stretching vibration of C=O (Fig. 3, curve b). ...
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This work concerns on the preparation and performance evaluation of a new chitosan hydroquinone based gauze for hemostatic use. Chitosan and hydroquinone were firstly connected by etherification and then linked to the pre-carboxylate gauze. The functionalized material and the chitosan-hydroquinone ether were characterized by Fourier Transform Infrared (FT-IR) Spectroscopy and Differential Scanning Calorimetry (DSC). FT-IR results showed that an esterification occurred on carboxylic group of the gauze. The gauze functionalization degree was also evaluated by volumetric analysis. The ether hydroquinone content was obtained by the Folin test. Moreover, the linkage between hydroquinone and chitosan was confirmed by nuclear magnetic resonance (NMR). The hemostatic activity of functionalized gauze was evaluated by dynamic blood clotting assays. The obtained results showed that the prepared material can shorten the blood clotting time and induce the adhesion and activation of platelets. Finally, swelling characteristic of the new gauze was evaluated to confirm its high capacity to absorb the blood.
... Classical synthesis of this kind of phenols can be performed by monoalkylation of hydroquinone with alkylating agents such as the dialkyl sulfate, haloalkanes, and alcohols, usually in the presence of acid or base catalytic conditions [5][6][7][8]. However, di-alkylation can also happen during the reaction and decrease the yield of the desired product. ...
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For synthesis of Mequinol (4-methoxy phenol), two acidic ionic liquids based on imidazolium cation (BMSIL and IMSIL) synthesized and characterized with FT-IR,¹H NMR and CHNS analyses. Then, the Baeyer–Villiger oxidation of para-anisaldehyde was studied with these ionic liquids, as the catalysts. The results showed that the BMSIL with more Brønsted acidic functions had higher catalytic activity than IMSIL and even sulfuric acid at room temperature. Furthermore, the different reaction parameters were studied and maximum conversion (99%) and selectivity (95%) of Mequinol was observed by using 5% BMSIL as catalyst, H2O2 (30% solution) as oxidant, Methanol as solvent at 3.5 h, and room temperature condition. Also, we investigated the effect of different substituents in the aromatic ring of benzaldehyde and various solvents on the catalytic activity of BMSIL ionic liquid as the best catalyst in the oxidation of aromatic aldehydes. The results show that the protic solvent and electron-donating substituents in para position of benzaldehyde favor the phenol product. © 2018, Iranian Journal of Chemistry and Chemical Engineering. All rights reserved.
O‐alkylation of a dihydric phenol (i.e., hydroquinone) with methanol in presence of benzoquinone catalyzed by double SO3H functionalized Brønsted acidic ionic liquids (i.e., 1,3‐disulphonic acid imidazolium hydrogen sulphate, 1,3‐disulphonic acid benzimidazolium hydrogen sulphate, and sulphuric acid) is studied in a batch reactor. The sensitivity of activity and selectivity with reaction time, temperature, speed of agitation, and catalyst loading was examined. The plausible reaction pathways proposed based on the experimental observations and detailed kinetic investigation are performed by assuming a homogeneous reaction phase. The kinetic parameters, such as pre‐exponential factor and activation energy, are estimated for both ionic liquids and sulphuric acid by considering all competitive reactions, and comparative results were presented. An extended form of the Arrhenius equation is used to estimate the kinetic parameters for the reaction which showed curvature in ln k against a 1/T plot. The model prediction with the estimated kinetic parameters is in good agreement with the experimental data, which confirmed the model validity in the experimental operating range. It was found that ionic liquid has a potential application in the synthesis of a selective monoalkylated product of hydroquinone. The kinetic analysis performed is found to be useful in the understanding of process behaviour.
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Protecting group chemistry has invariably captured the fascination of chemists because of its extensive viability in chemical synthesis. The present report describes our pioneer work of applying ytterbium triflate as a catalyst, for the reaction of alcohols with di-tert-butyl dicarbonate (Boc2O) leading to the formation of tert-butyl ethers. There exists no recorded evidence for the use of Yb(OTf)3 as a catalyst for the protection of alcohols to tert-butyl ethers, despite its excellent utility in various reactions. Yb(OTf)3 has been used predominantly in the catalytic deprotection studies such as selective deprotection of tert-butyl esters to carboxylic acids as well as prenyl ethers to alcohols. This study involved the critical evaluation of solvent, time, and temperature that finally led to an efficient protocol for the formation of tert-butyl ethers. Yb(OTf)3 catalyzed the formation of tert-butyl ethers, notably reducing the reaction time, which is exemplified by the achievement of up to 92% conversion of alcohols to tert-butyl ethers within an hour. Additionally, the report demonstrates the utility of this synthetic protocol for the protection of carboxylic acids.
A process aiming at O-alkylation of hydroquinone (HQ), where ionic liquids (ILs) act as catalyst is objectively described. Five SO3H-functionalized ILs having different cations were prepared and characterized by NMR and FTIR techniques. The acidity and thermal stability of ILs were determined by Hammett function and thermogravimetric analysis (TGA), respectively. The catalytic activity of these ILs were tested for O-alkylation of HQ with methanol in 4-methoxyphenol (4MP) in the presence of small amount of benzoquinone (BQ). The effect of reaction parameters such as temperature, time, catalyst loading and substrate concentration on the conversion of HQ and product distribution was examined and optimized to maximize the yield of 4MP using 1,3-disulfonic acid imidazolium hydrogen sulfate (IL2) catalyst. Maximum yield of desired product 4MP 93.79% was obtained at 338 K temperature, 5.45 × 10–2 mol HQ, 8.33 × 10–3 mol BQ, and 10.37 mol% catalyst loading in 120 min reaction time. Single-product formation was observed up to 338 K temperature but higher temperature (above 338 K) and longer reaction time resulted in the formation of 2,4-dimethoxyphenol (24DMP) as a by-product. Catalyst recyclability was also established up to the fifth run which showed no declination in its activity.
‐ Sodium nitrite (NaNO2) is a cheap inorganic reagent that has wide applications in synthetic organic chemistry. Sandmeyer reaction for transforming amines into diazo derivatives and nitration including the oxidative ones are well known and globally used in several industrial processes too. It is also used in the Nef reaction and Abidi transformation besides several other important reactions. The property of the NaNO2 to produce NO˙, NO2 and N2O4 under the oxidative conditions has considerably assisted to discover its newer applications. Strikingly, this has resulted in remarkable development in reactions involving NaNO2 as either catalyst or reagent and this review is an attempt to assimilate them. Wherever possible the mechanistic details associated with the reported reaction/ tranformation is provided. The review is discussed under the following sub headings
The synthesis of carbon nanotube (CNT) fragments has long captivated organic chemists, despite the simplistic, symmetric nature of the requisite achiral targets. Such molecules hold the potential to allow for the synthesis of homogeneous CNTs, rendering their properties more suitable for advanced applications in electronics and sensing. The [n]cycloparaphenylene family, comprised of molecules with para-linked phenyl rings in a contiguous macrocycles, represents a major landmark towards achieving absolute control of CNT architecture from the bottom-up. Attempts towards accessing the [n]cyclacene and [n]cyclophenacene families, both of which are comprised of double-stranded macrocyclic belts, have only recently been successful, however. These targets have been plagued by unstable, strained intermediates and stereochemical pitfalls that have largely thwarted accessing these fascinating structures. Herein, we disclose our synthetic strategy toward overcoming several stereochemical challenges en route to [n]cyclophenacenes via highly substituted [n]cycloparaphenylene precursors.
O-alkylation reaction of hydroquinone with excess methanol was performed by using alkali metal ion-exchanged zeolite catalysts in a slurry type reactor to substitute the solid zeolite catalysts for the homogeneous liquid phase catalysts. This was also done to produce selectively mono-alkylated 4-methoxyphenol, a valuable intermediate for the perfume, flavor, food and photo industries. The effects of the basicity of various zeolites and reaction conditions such as temperature, reaction time and the amount of catalyst on the catalytic activity and selectivity were tested to maximize the yield of 4-methoxyphenol. Thus far, 84% selectivity at 95% conversion of hydroquinone was obtained at the optimum reaction conditions (240 ‡C, reaction with 0.6 g catalyst for 16 h), which was thought to result from the strong basic property and shape selectivity of the Cs ion-exchanged NaX zeolite.
The alkylation of phenol derivatives can be achieved in good yield via Lewis or Brønsted acid. The only by-product of the reaction is water and the catalyst can be recycled when using Brønsted acid.
Naphthohydrochinon (2a) reagiert unter Katalyse von Chlorwasserstoff oder Thionylchlorid über das tautomere 2,3-Dihydronaphthochinon (9) mit primären und sekundären Alkoholen in hoher Ausbeute zu den Naphthohydrochinon-monoalkylethern 2b-n. Der Einfluß von Substituenten auf die Regioselektivität der Reaktion wird untersucht.Dimeric Naphthoquinones, II1) – Simple and Regioselective Synthesis of Naphthoquinol Monoalkyl Ethers via 2,3-DihydronaphthoquinonesOn catalysis of hydrogen chloride or thionyl chloride, 1,4-naphthalenediole (2 a) reacts with primary or secundary alcohols via the tautomeric 2,3-dihydronaphthoquinone (9) to give naphthoquinol monoalkyl ethers 2b – n in high yields. The influence of the substitution pattern on the regioselectivity of the reaction has been investigated.
IT is known that quinhydrones are weak acids and may therefore form ions in strongly alkaline solutions. Due to the loss of two hydrogen atoms of the quinhydrone compound, two identical semiquinone ions can be expected; for example: These semiquinone ions, having an odd number of electrons, should be paramagnetic. Michaelis has proved the existence of free radical ions of this type during alkaline reduction of phenanthrene-quinone-3-sulphonate1 by potentiometric and magnetic measurements. It would be difficult to demonstrate the existence of free radical ions in the case of many quinhydrones, for example, p-benzoquinhydrone, as they are too unstable in alkaline solution. It occurred to us, however, that it might be possible to stabilize such unstable radical ions by adsorption of quinhydrone on suitable basic surfaces. A sufficiently basic surface could have the same effect as the alkaline solution, and the adsorption might stabilize the free radicals formed.
An efficient catalytic method is described for the preparative conversion of hydroquinones to quinones with dioxygen under mild conditions. The use of the gaseous nitrogen oxide (NOx) catalyst allows a simple workup procedure for the isolation of quinones in essentially quantitative yields by merely removing the low-boiling solvent dichloromethane in vacuo. The mechanism of the catalytic autoxidation of hydroquinones is ascribed to the critical role of nitrosonium (NO+) in the one-electron oxidation of hydroquinone, followed by the reoxidation of the reduced nitric oxide (NO) with dioxygen. An extensive series of complex interchanges among various NOx species in nitrogen-(V), -(IV), -(III), and -(II) oxidation states, coupled with stepwise oxidation of hydroquinone via a successive series of one-electron/proton transfers, form the critical components of the catalytic cycle.
Hydroquinone mono methyl ether (HMME) is industrially a very important anti-oxidant, produced by environmentally undesirable routes. In the current studies, HMME was synthesized from hydroquinone and methanol catalyzed by various solid acids using montmorillonite clay (K10) as a support with different loadings of dodecatungstophosphoric acid (DTP), AlCl3, FeCl3, and ZnCl2. Among these, 40% DTP/K10 with benzoquinone as cocatalyst was the most active and selective. The reaction mechanism suggests that benzoquinone couples with protonated methanol on the catalyst site to yield an intermediate, which reacts with hydroquinone adjacent to the site. The surface reaction between the intermediate and chemisorbed hydroquinone controls the overall rate of reaction. There is 100% selectivity toward HMME. The experimental data are well correlated with the model. Excess of methanol favors the formation of HMME.
A range of allyl-functionalized cyanate ester oligomers (and their precursors) containing four and six phenylene groups in the backbone were prepared in high yield and characterized using H-1 and (1)3C nuclear magnetic resonance (NMR) spectroscopy and microanalysis. The thermally-initiated polymerization of the monomers was studied using differential scanning calorimetry (DSC) and the kinetic parameters of the reaction obtained: the polycyclotrimerization was extremely well-fitted to a first-order model over the apparent conversion range 5-50% (yielding Arrhenius parameters as apparent activation energies of 211.7 kJ mol(-1) and In A = 39.8 for 6 and 148.1 kJ mol(-1) and in A = 27.0 for 12). The effect of increasing allyl-functionalized cyanate ester content upon a commercial cyanate ester/bis(maleimide) blend was examined using DSC, giving further evidence of a coreaction. The thermal-oxidative stability of the polymeric blends and terpolymers was investigated using thermogravimetric analysis (TGA) and revealed that incorporation of functionalized oligomeric cyanate esters (ranging between 12.5 and 50%) into bis(maleimide) networks can be achieved without dramatic stability penalties.
A method for the oxidation of organotrifluoroborates using Oxone was developed. A variety of aryl-, heteroaryl-, alkenyl-, and alkyltrifluoroborates were converted into the corresponding oxidized products in excellent yields. This method proved to be tolerant of a broad range of functional groups, and in secondary alkyl substrates it was demonstrated to be completely stereospecific.
A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascular liabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linker as the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and 1-(S) induced gene expression patterns similar to that seen with several known cardiotoxic agents such as doxorubicin. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitors with drastically improved cardiovascular and neurological profiles.