Selective Monoetherification of 1,4-Hydroquinone Promoted by NaNO2

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 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.
INTRODUCTION
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, 7 – 20131
Milano, Italy; Tel: +39 0223994748; Fax: +39 02 23993180;
E-mail: cristian.gambarotti@polimi.it
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.
EXPERIMENTAL SECTION
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 100L 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.
RESULTS AND DISCUSSION
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.
OH
OH
O
OO
O
.O
O
.
2+2 H+2
NaNO2
H2SO4
OR
OH
OH
OH
+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-
ditions.
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.
O
O H
OH
O H
NaNO2HNO2
NO2NO
.
NO2
2 HNO2H2O
++
(1)
H+ cat.
(3)
(2)

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.
O
O
COH
H
HH
OHCH
3O
OMe
OMe
H
OH
OMe
OMe
H2O
O
O H
O
O H
.
.
O
O H
O
O
..
+H2O
-
+H
3O+
OH
OH
ROH
O
O
R
.
O
OH
R
O
OH
.H2O

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.
CONCLUSION
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
OH OH
2a
rt 1 100 >99
OH OMe
3a
92
2a, [12] Ethanol 1b
OH OH
2a
rt 3 100 93
OH OEt
3b
89
3 [13] 1-Butanol 1c
OH OH
2a
rt 72 95 >99
OH OBu
3c
86
4b, [14] Benzyl alcohol 1d
OH OH
2a
rt 24 87 86
OH OBz
3d
75
5 [15] iso-Propanol 1e
OH OH
2a
rt 24 95 >99
OH O
3e
85
6 [16] Allyl alcohol 1f
OH OH
2a
rt 24 99 98
OH O
3f
90
7b, [17] Cyclohexanol 1g
OH OH
2a
rt 48 90 >99
OH OCy
3g
80
8tert-Butanol 1h
OH OH
2a
rt 48 48 63
OH O
3h
22
9 Propargyl alcohol 1i
OH OH
2a
rt 3 100 45
OH O
3i
39
10c Methanol 1a
OH OH
2b
rt 3 100 70
OH OMe
3j
63
11c Methanol 1a
OH OH
2c
rt 3 100 87
OH OMe
3k
78
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.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
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
spectra.
SUPPLEMENTARY MATERIAL
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