Electrochemical SNH(An) functionalization of 1,2- and 1,4-dihydroxybenzenes

Article abstract of DOI:10.1016/j.mencom.2016.11.028

The regularities of electrochemical S_N^H(An) functionalization of 1,2- and 1,4-dihydroxybenzenes with nucleophiles of various strength and basicity are characterized.

Full text of DOI:10.1016/j.mencom.2016.11.028

Mendeleev
Communications
Mendeleev Commun., 2016, 26, 540–542
Electrochemical SHN(An) functionalization
of 1,2- and 1,4-dihydroxybenzenes
Vladimir A. Kokorekin, Yaroslav A. Solomatin, Marina L. Gening and Vladimir A. Petrosyan*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
E-mail: petros@ioc.ac.ru
DOI: 10.1016/j.mencom.2016.11.028
Nu
Nu
O
O
HO
(weak base)
The regularities of electrochemical SHN(An) functionalization
of 1,2- and 1,4-dihydroxybenzenes with nucleophiles of various
strength and basicity are characterized.
[– e]
H
O
OH
HO
Nu
(strong base)
A mixture
of polymeric
products
[– e]
OH
OH
Dihydroxybenzenes (DHB) are constituents of various pharma-
cologically active compounds.1–4 Their electrochemical modi-
fication with various nucleophiles (azides,5 alcohols,6 amines,7
thiols,1 etc.) using an anode as a ‘green oxidizing agent’ has
been intensely studied in recent years. Such processes should
be considered8,9 as electro-induced nucleophilic substitution of
hydrogen in an arene [SNH(An)] occurring through generation
of a quinone followed by Michael addition (Scheme 1).
potential (Epox) of Nu, whose nucleophilicity should decrease with
rising Epox (cf. refs. 10, 11). In total, the efficiency of the process
turned to be substrate dependent.
Mercaptobenzotriazole 3 with lowest Epox = 1.3 V was the
most efficient among other nucleophiles and the yields of its
derivatives 6 and 9 were reasonable (see Table 1). Let us also
note that the reactivity of electrogenerated poorly stable o-benzo-
quinone towards 3 was much higher than that in the case of
p-benzoquinone. That is why the final solutions contain, along
OH
OH
O
OH
OH
– 2e
– 2H+
Nu– H+
SH
S
OH
O
OH
O
N
OH
O
H
O
Nu
Scheme 1
OH
Epox = 1.1 V
1
O
Epox = 1.3 V
Epox = 1.3 V
Scheme 1 describes the process just formally. It is no coin-
cidence that neutral or weakly acidic (but not alkaline) solutions
are actually more beneficial for DHB electrofunctionalization
in aqueous media (see e.g. ref. 7). However, the studies cited
above did not give proper attention to analysis of the reasons
why the acidic properties of the medium, i.e., DHB as such, as
well as the basic properties of the Nu, affect the course of the
process. Here, we made an attempt to clarify these problems.
We took into consideration data on controlled potential elec-
trolysis (CPE) of hydroquinone 1 and pyrocatechol as DHB
in MeCN in the presence of some representative nucleophiles
(Figure 1), as well as data on cyclic voltammetry (CV) of these
co-reagents under the same conditions. As nucleophiles with
various basic properties, the following compounds were chosen:
2-mercaptobenzothiazole 3, 4-nitropyrazole sodium salt 4 and
3,5-dimethylpyrazole 5.† The results are summarized in Table 1.
As seen from Table 1, the efficiency of the process (see
Scheme 1) diminishes with an increase in the oxidation peak
1'
2
2'
3
O2N
Me
N
OH
S
N
N
Me
Na+ N
N
H
S
Epox = 1.6 V
Epox = 1.8 V
OH
4
5
6
NO2
Me
OH
OH
OH
OH
Me
N
N
N
HO
N
S
N
S
OH
7
8
9
Figure 1 Reactants 1–5 with their oxidation potentials vs. SCE and
products 6–9 obtained.
†
1H NMR spectra were recorded in DMSO-d6 on a Bruker Avance 300
Light petroleum, EtOAc, MeCN, MeOH, NaClO4, hydroquinone 1,
pyrocatechol 2, 2-mercaptobenzothiazole 3, 4-nitro-1H-pyrazole, 3,5-di-
methyl-1H-pyrazole 5, ButOK and silica gel (0.035–0.070 mm, 60 Å) for
column chromatography were purchased from Acros Organics. Sodium
4-nitropyrazolate 4 was obtained according to a reported procedure.14
Electrolysis of DHB in the presence of a nucleophile (Table 1, entries
1 and 3). A solution of NaClO4 in MeCN (50 ml, 0.1 m) containing
0.001 mol of DHB and 0.002 mol of a nucleophile was placed in the
anodic space of a spatially divided (by a diaphragm made of tracing paper)
instrument (300.13 MHz). Mass spectra were recorded using a Finnigan
MAT INCOS 50 instrument. Voltammetric (CVA) studies were carried out
in a temperature-controlled (25°C) cell (V = 10 ml) using an Elins P30JM
potentiostat (the scan rate was 0.1V s–1).A platinum wire 1 mm in diameter
in a Teflon casing was used as the working electrode. A saturated calomel
electrode (SCE) separated from the solution by a salt bridge filled with the
supporting electrolyte (0.1 m NaClO4 in MeCN) was used as the reference
electrode. A platinum plate (S = 3 cm2) was used as the counter electrode.
© 2016 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2016, 26, 540–542
Table 1 Electrolysis of DHB in the presence of nucleophiles.
Product with nucleophiles [yield (%)]
HO
OH
Entry Substrate ECPE/V
1
pathway a
– 2e, – 2H+
pathway b
Nu–
3
4
5
c
1
2
3
1
1'd
1.1
–
6 (13,a 10b)
6 (10,a 8b)
9 (35,a 30b)
–
8 (6a)
8 (5a)
– NuH
7 (4a)
O
O
c
c
2
1.3
–
–
pathway a'
pathway c
a NMR yield. b Isolated yield. cA complex mixture of products; the same
result was obtained at ECPE = 0.4 V. d p-Benzoquinone 1' was preliminarily
generated from 1 followed by addition of Nu.
O
OH
OH
1'
Nu–
1–
NuH
– e
H
H
NuH
H
Nu
with the target thioether 6, up to 85% of non-reacted 1', whereas
no unreacted 2' was found in the final solution in the preparation
of thioether 9.
On can believe that oxidative functionalization of p(o)-DHBs
in the presence of 3 occurs through pathway a (Scheme 2). The
initial stage of this process corresponds to the electrogeneration
of quinone 1', which adds NuH and, according to the published
data,12 gives the target product A.
O
O
O
O
O
O
B–
1
Nu
H+
+ 1 (+ 1')
If the nucleophile is charged (Nu–), then, depending on its
basicity, the process can occur either by pathway b or by path-
way a' (see Scheme 2). In the latter case, product A can be
deprotonated with Nu–, and the resulting anion A– (a tautomer
of anion B–) can undergo subsequent transformations, e.g., via
pathway c. Let us note that deprotonation can also occur in the
case of a non-charged but sufficiently basic NuH. Thus, the role
of acid-base properties of the co-reactant (and also medium) is an
important factor (see pathways a, a', b and c).
OH
[– e]
Nu
Nu
Nu–
HO
HO
(NuH)
A mixture
of polymeric
products
– NuH
OH (NuH+)
O
A
A–
Scheme 2
Unlike thiol 3, the nitropyrazole salt 4 is not only a weaker
nucleophile (Epox = 1.6 V, see Figure 1), but also, much more
important, has higher basicity (CV data, see below). Its processing
apparently occurs by pathway b (see Scheme 2), the first stage of
which (1 ® 1– ) corresponds to deprotonation of the starting 1.
Anion 1– is oxidized much more easily than the starting 1, and
reactions with the starting 1, with quinone 1', etc.). This, as a
rule, gives a complex mixture of products. This mechanism
agrees with the experimental results provided below.
The CV data for mixtures of 1 (pKa = 9.85)7/4 and 2 (pKa =
= 9.27)13/4 confirmed that the anion of salt 4 had the properties
of a base (Scheme 3). In fact, the heights of o(p)-DHBs oxidation
peaks in the presence of this anion would decrease (see, e.g.,
o-DHB 2, peak 1, Figure 2), and a new peak 2 with Epox = 0.4 V
·
the resulting radical 1 undergoes various transformations (by
thermally controlled (25°C) cell (V = 60 ml) with coaxial cylindrical
Pt electrodes (Sanode = 26 cm2, Scathode = 10 cm2). In the tests with salt 4,
MeOH (2 ml) was added to ensure complete dissolution. A 0.1 m solution
of NaClO4 in MeCN (10 ml) was placed in the cathodic space. Electrolysis
was carried out in a flow of nitrogen with vigorous stirring at oxidation
potentials of 1.1 V (1), 1.3 V (2) or 0.4 V [p(o)-DHB– anions]. The process
was stopped at regular intervals for reactivation of the Pt electrodes by
calcination and for addition of fresh portions of the catholyte. After
passing 2 F of electricity (as required for a 2-electron process of DHB
oxidation), electrolysis was stopped and the mixture was stirred for 2 h.
The solvent was distilled off in vacuo, then water (10 ml) was added and
the mixture was sequentially extracted with toluene (2×30 ml) and Et2O
(2×30 ml). The extracts were combined, dried (Na2SO4), filtered and
concentrated in vacuo. The residue was analyzed by mass spectrometry
and 1H NMR spectroscopy with addition of dioxane as the standard (all
experiments) or purified by column chromatography on SiO2 using the
light petroleum/EtOAc system (experiments with 3). In the first case,
the product yield was determined from 1H NMR data by comparison of
the integral intensities of the signals of CH-protons in the product (in the
range of d 5.5–7.2) and CH2-protons in dioxane (at d 3.70). Identification
of the products was performed using their characteristics reported pre-
viously (in the case of products 6 and 9),15,16 or (for new compounds 7
and 8) based on the known characteristics of compounds with similar
structures, namely: 2-bromobenzene-1,4-diol,17 1-(2,5-dimethoxyphenyl)-
4-nitro-1H-pyrazole and 1-(2,5-dimethoxyphenyl)-3,5-dimethyl-1H-
pyrazole.18
2-(1,3-Benzothiazol-2-ylsulfanyl)benzene-1,4-diol 6: white solid,
mp 224–226°C. 1H NMR, d: 6.88 (dd, 1H, C5H, J5,6 8.8 Hz, J5,3 2.7 Hz),
6.93 (dd, 1H, C6H, J6,5 8.8 Hz, J6,3 0.6 Hz), 7.02 (dd, J3,5 2.7 Hz, J3,6 0.6 Hz),
7.29 (ddd, 1H, C6'H, 2-C7H4NS2, J6',7' 8.2 Hz, J6',5' 7.1 Hz, J6',4' 1.1 Hz),
7.42 (ddd, 1H, C5'H, 2-C7H4NS2, J5',4' 8.1 Hz, J5',6' 7.1 Hz, J5',7' 1.2 Hz),
7.82 (ddd, 1H, C4'H, 2-C7H4NS2, J4',5' 8.1 Hz, J4',6' 1.1 Hz, J4',7' 0.7 Hz),
7.90 (ddd, 1H, C4'H, 2-C7H4NS2, J7',6' 8.2 Hz, J7',5' 1.2 Hz, J7',4' 0.7 Hz),
9.20 (br.s, 1H, 4-OH), 9.68 (s, 1H, 1-OH). MS, m/z: 275 (M+). Found (%):
C, 56.82; H, 3.19; N, 5.14. Calc. for C13H9NO2S2 (%): C, 56.71; H, 3.29;
N, 5.09.
2-(4-Nitro-1H-pyrazol-1-yl)benzene-1,4-diol 7: 1H NMR, d: 6.70 (dd,
1H, C5H, J5,6 8.8 Hz, J5,3 2.6 Hz), 6.91 (d, 1H, C6H, J6,5 8.8 Hz), 7.09
(d, 1H, C3H, J3,5 2.6 Hz), 8.48 (s, 1H, 2-C3H2N3O2, C5'H), 9.16 (s, 1H,
2-C3H2N3O2, C3'H), 9.21 (br.s, 1H, 4-OH), 9.98 (br.s, 1H, 1-OH). MS,
m/z: 221 (M+).
2-(3,5-Dimethyl-1H-pyrazol-1-yl)benzene-1,4-diol 8: 1H NMR, d: 2.07
(s, 3H, 2-C5H7N2, 5'-Me), 2.15 (s, 3H, 2-C5H7N2, 3'-Me), 5.98 (s, 1H,
2-C5H7N2, C4'H), 6.60 (d, 1H, C3H, J3,5 2.3 Hz), 6.69 (dd, 1H, C5H,
J5,6 8.8 Hz, J5,3 2.3 Hz), 6.81 (d, 1H, C6H, J6,5 8.8 Hz), 9.50 (br.s, 2H,
1-OH, 4-OH). MS, m/z: 204 (M+).
4-(1,3-Benzothiazol-2-ylsulfanyl)benzene-1,2-diol 9: pale yellow solid,
mp 196–198°C. 1H NMR, d: 6.93 (dd, 1H, C6H, J6,5 8.2 Hz, J6,3 0.7 Hz),
7.07 (dd, 1H, C5H, J5,6 8.2 Hz, J5-3 2.2 Hz), 7.14 (dd, 1H, C3H, J3,5 2.2 Hz,
J3,6 0.7 Hz), 7.29 (ddd, 1H, C6'H, 2-C7H4NS2, J6',7' 8.2 Hz, J6',5' 7.1 Hz,
J6',4' 1.2 Hz), 7.41 (ddd, 1H, C5'H, 2-C7H4NS2, J5',4' 8.2 Hz, J5',6' 7.1 Hz,
J5',7' 1.2 Hz), 7.80 (ddd, 1H, C4'H, 2-C7H4NS2, J4',5' 8.2 Hz, J4',6' 1.1 Hz,
J4',7' 0.7 Hz), 7.89 (ddd, 1H, C4'H, 2-C7H4NS2, J7',6' 8.1 Hz, J7',5' 1.2 Hz,
J7',4' 0.7 Hz), 9.57 (br.s, 1H, 4-OH), 9.77 (s, 1H, 1-OH). MS, m/z: 275
(M+). Found (%): C, 56.84; H, 3.16; N, 5.17. Calc. for C13H9NO2S2 (%):
C, 56.71; H, 3.29; N, 5.09.
Electrosynthesis of benzoquinone 1' followed by the nucleophile addition
(Table 1, entry 2). The process was carried out under the conditions
described above, in two stages: (1) electrolysis of 0.001 mol of 1 by passing
2 F electricity (as required for 2-electron oxidation); (2) addition of
0.002 mol of a nucleophile (3–5) with stirring for 2 h. The resulting
mixture was treated and analyzed as above.
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Mendeleev Commun., 2016, 26, 540–542
o-DHB–
electrolysis of p-DHB 1 in the presence of 5 (or addition of 5 to
60
50
o-DHB
benzoquinone 1') affords the azolation product 8 in only 5–6%
yields, along with up to 80% unreacted 5 (see Table 1). This
result is apparently a consequence of both the insufficient nucleo-
philicity of 5 and its weaker basic properties in comparison with
anion of salt 4. The absence of 5 in the reaction mixture after the
electrolysis of o-DHB 2 (entry 3) indicates that 5 is consumed
somehow to give polymeric products.
In conclusion, without optimizing the conditions of studied
SNH(An) processes involving DHB/Nu pairs, their main regularities
were established. In general, one of the important conditions for
successful electrofunctionalization of DHB is that the substituting
reactant should be not only a strong nucleophile but also a rather
weak base which cannot deprotonate either the starting DHB or
their functionalization products. The balance of the acid-base
properties of nucleophile, DHB, and the medium are the key factor
here. This balance should be regarded thoroughly in each case to
develop an efficient process of DHB functionalization.
2
1
40
30
20
10
0
–10
–20
o-Benzoquinone
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0
E vs. SCE/V
Figure 2 CV of o-DHB 2 (c = 0.002 m) on a Pt electrode (1) in 0.1 m
NaClO4 solution in MeCN and (2) in the presence of an excess of salt 4
(c = 0.008 m).
appeared simultaneously. With a 4-fold excess of salt 4 the
oxidation peaks of o(p)-DHBs completely disappeared, whereas
the peak with Epox = 0.4 V remained. A similar CV analysis of
o(p)-DHB solutions with the addition of ButOK confirmed that
the anodic peak with Epox = 0.4 V corresponded to o(p)-DHB–
monoanions oxidized at the same potential.
This study was supported by the Russian Science Foundation
(grant no. 14-50-00126).
References
NO2
Na+
OH
O
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– HAz
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2
N
OH
Epox = 0.4 V
Na+
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4
Scheme 3
Note that on addition of an excess of salt 4 to a solution
of o(p)-DHB in MeCN, the solution turned dark red, which
indicated that o(p)-DHB– ions were formed (see Scheme 3).
Electrolysis of these mixtures (see Table 1, entries 1 and 3) gave
resinous products. Thus, it is undesirable to perform the process
by pathway b (see Scheme 2) involving o(p)-DHB– anions. An
attempt to redirect the process from pathway b to pathway a' by
preliminary electrogeneration of quinone followed by addition
of salt 4 did not lead to a noticeable success, either. Apparently,
protons are scavenged in the anolyte by the excess basic anion
of 4, which inhibits the protonation stage (pathway a'). As a
consequence, intermediate anion B– undergoes various reactions
(e.g., reacts with quinone) to give resinous products. For these
reasons, azolation product 7 was detected in the reaction mixture
1
by H NMR spectroscopy and mass spectrometry, although in
trace amounts, and only in the case of the more stable benzo-
quinone 1' (see Table 1, entry 2).
16 H. T. Abdel-Mohsen, J. Conrad and U. Beifuss, Green Chem., 2014,
16, 90.
Even if one assumes that product A can be formed (see
Scheme 2), then, due to the acceptor properties of the nitro-
pyrazole substituent, this product should undergo deprotonation
more easily than the starting DHB, with generation of anion A–
followed by its resinification, e.g., by pathway c. On the other hand,
as expected, suppression of the basic properties of salt 4 anion
by addition of an acid resulted in its nearly complete deactivation.
As expected, in the case of pyrazole 5 (Epox = 1.8 V) the
efficiency of reactions with DHBs was low (see Table 1). In fact,
17 J. Wang, W. Wang and J.-H. Li, Green Chem., 2010, 12, 2124.
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2001, 1215).
Received: 10th May 2016; Com. 16/4932
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