Complexes of copper(I) with aromatic compounds facilitate selective electrophilic aromatic substitution

Article abstract of DOI:10.1080/00958972.2018.1490415

We report on the selective formation of ortho-nitrophenol, ortho-nitrotoluene (1-Methyl-2-nitrobenzene) and ortho-phenolsulfonic acid (2-Hydroxybenzenesulfonic acid) through reaction of the Cu(I)-aromatic ring complex of phenol or toluene. In the case of nitration of phenol, the reaction could be formulated as: (Figure presented.) The copper(I)-aromatic ring complex is formed in situ from Cu(II) and metallic copper in deaerated aqueous solutions containing the aromatic compounds. Phenol or toluene shift the comproportionation reaction of copper(0) and copper(II) towards the formation of Cu(I): (Formula presented.) The stability constant of Cu(I)-phenol in aqueous solutions was reported previously as 900 ± 100 M^?1. The surprisingly stable d?π* Cu(I)-phenol complex causes distortion of the ring structure which facilitates selective substitutions. Similar results are reported for sulfonation of phenol (in aqueous solutions) and for nitration and sulfonation of toluene in a two phase process.

Full text of DOI:10.1080/00958972.2018.1490415

Journal of Coordination Chemistry
ISSN: 0095-8972 (Print) 1029-0389 (Online) Journal homepage: http://www.tandfonline.com/loi/gcoo20
Complexes of copper(I) with aromatic compounds
facilitate selective electrophilic aromatic
substitution
Magal Saphier, Inna Levitsky, Alexandra Masarwa & Oshra Saphier
To cite this article: Magal Saphier, Inna Levitsky, Alexandra Masarwa & Oshra Saphier (2018):
Complexes of copper(I) with aromatic compounds facilitate selective electrophilic aromatic
substitution, Journal of Coordination Chemistry, DOI: 10.1080/00958972.2018.1490415
To link to this article: https://doi.org/10.1080/00958972.2018.1490415
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Complexes of copper(I) with aromatic compounds facilitate selective
electrophilic aromatic substitution
MAGAL SAPHIER*†, INNA LEVITSKY‡, ALEXANDRA MASARWA§ and OSHRA SAPHIER‡
†Chemistry Dept., Nuclear Research Centre Negev, Beer-Sheva, Israel
‡Chemical Engineering Dept., Sami Shamoon College of Engineering of the Negev, Israel
§Chemistry Dept., Ben Gurion University of the Negev, Israel
We report on the selective formation of ortho-nitrophenol, ortho-nitrotoluene (1-Methyl-
2-nitrobenzene) and ortho-phenolsulfonic acid (2-Hydroxybenzenesulfonic acid) through
reaction of the Cu(I)-aromatic ring complex of phenol or toluene.
In the case of nitration of phenol, the reaction could be formulated as:
The copper(I)-aromatic ring complex is formed in situ from Cu(II) and metallic copper in
deaerated aqueous solutions containing the aromatic compounds. Phenol or toluene shift the
comproportionation reaction of copper(0) and copper(II) towards the formation of Cu(I):
2C6H5OH(aq) + Cu2+(aq) + Cu0
2CuI(C6H5OH)+
(aq)
(s)
The stability constant of Cu(I)-phenol in aqueous solutions was reported previously as
900±100 M-1. The surprisingly stable d* Cu(I)-phenol complex causes distortion of the ring
structure which facilitates selective substitutions.
Similar results are reported for sulfonation of phenol (in aqueous solutions) and for
nitration and sulfonation of toluene in a two phase process.
Keywords: Monovalent copper,  Complex; Aromatic substitution
*Corresponding author. Email: magal_saphier@yahoo.com
1

INTRODUCTION
Complexes of copper(I) with aromatic compounds, benzoic acids and phenol, in aqueous
solutions have been studied. Based on published experimental results (NMR, ESR, UV-Vis and
electrochemistry) [1], it is clear that the complexes formed between Cu(I) and phenol and
benzoic acid are due to d* interactions between the copper d orbitals and the aromatic 
system and not with the oxygen. The stability constant of Cu(I)-phenol in aqueous solutions was
900100 M-1 [1].
Quantum mechanical calculations of the structure of the Cu(I)-phenol complex [2]
(figure 1) indicate that copper(I) is bound mainly to one carbon-carbon bond of the ring and that
the carbon hydrogen bond ortho to the hydroxyl group is elongated, 1.113 Å, compared to the
para bound, 1.090 Å, and native phenol, 1.094 Å. Furthermore, all the carbon-carbon bonds in
the complex are elongated by ~0.04 Å compared to the native phenol. The crystal structure of
Cu(I)(C6H6) [3] supports the quantum mechanical calculations. In the crystal structure copper(I)
is bound mainly to one carbon-carbon bond, the benzene ring in the complex is distorted and
distances between carbons vary from 1.25 Å to 1.41 Å. The calculated structure of the Cu(I)-
phenol complex and the crystal structure of Cu(I)(C6H6) can be explained by charge transfer
from the low bonding orbital of the aromatic system to the positively charged Cu+, and back
donation from the fully occupied d orbitals of the monovalent copper to the * anti-bonding
orbital of the aromatic system (figure 2). The localization of the charge on the * anti-bonding
orbital resembles an excited state of the aromatic system and may cause distortion of the ring
structure and facilitate selective substitutions. That finding supports the reported role of
copper(I) in the Ullmann reaction mechanism [4] which involves two copper(I) ions, one
interacts and activates the aromatic system and the second substitutes the "ortho" atom (bromine
in the article) to form a copper-carbon intermediate. This intermediate reacts very rapidly with
the substituent (OH- in the article) to form the ortho isomer exclusively.
The importance of the electronic state for aromatic substitution can be supported by a
computational study [5], which shows that the loss of aromaticity and -electron delocalization is
the first step in the electrophilic aromatic nitration of benzene, phenol and benzonitrile. The
transition structures and the -complexes associated with the nitration of aryl compounds reflect
an almost complete destruction of the aromaticity of the starting arenes as well as a strong -
electron delocalization.
2

The mechanism of the aromatic nitration substitution reaction was studied intensively
over the years; it proceeds as an electrophilic substitution reaction that occurs with the active
+
+
intermediate nitronium ion, NO2 . Brønsted acid sites are responsible for the generation of NO2
from nitric acid. Thus the catalytic activity depends on Brønsted acidity. Brei et al. [6] explained
+
that strong Brønsted sites are necessary for an effective formation of intermediate NO2 ions
from nitric acid. Furthermore, Mishra et al. [7] reported that Brønsted acid sites are responsible
+
for the NO2 formation while Lewis sites favor the formation of para substituted product.
+
Generation of NO2 ion in concentrated nitric acid:
+
-
2HNO3
NO2 + NO3 + H2O
Sulfuric acid shifts the equilibrium to the right via:
+
-
2HNO3 + H2SO4
H2NO3 + HSO4
+
+
-
H2NO3 + H2SO4
NO2 + H3O+ + HSO4
The nitration is described in the literature as an SN1 type addition-elimination mechanism
for electrophilic aromatic substitution. The hydroxyl group on phenol is an ortho-para director
due to the electron-donating character of the hydroxyl group which has the potential to stabilize
the cyclohexadienyl cation intermediate. The ratio in the concentrated nitric acid reaction is 55%
o-nitrophenol, <1% m-nitrophenol and 45% p-nitrophenol [8].
Nitration of aromatic compounds is an industrially consequential reaction as the nitrated
products are important intermediates for fine chemicals and pharmaceuticals. Generally, nitration
reactions are not selective and are the cause of environmental concerns regarding the disposal of
the large excess of mixed acids employed in these processes.
The replacement of current chemical processing techniques with more environmentally
friendly and selective alternatives is an increasingly attractive subject. Using catalyst on solid
support it was found that the nitration of phenol is selective under mild conditions [9-13]. For
example, Khder et al. [9] show selective nitration of phenol over nanosized tungsten oxide
supported on sulfated SnO2 as a solid acid catalyst, Yin and Shi [10] report nitration of
substituted phenols by metal salts impregnated with Yb-Mo-Montmorillonite, and Mallick and
Parida [11] present selective nitration of phenol over silicotungstic acid supported on zirconia.
3

Sasson et al. [14] employed a liquid-liquid two-phase system with a phase-transfer
catalyst, tetrabutylammonium bromide (TBAB), to achieve highly selective nitration of phenol to
ortho-nitrophenol under mild conditions with dilute nitric acid (6 wt %).
Copper is mentioned in the literature related to the nitration of phenol; Ghalsasi et al. [15]
used Cu(NO3)2 in glacial acetic acid as source of HNO3.
Ga Young Park et al. [16] report on the reaction of nitrogen monoxide with a copper(I)
complex possessing a tridentate alkylamine ligand yielding a Cu(I)–(NO) adduct, which when
exposed to dioxygen generates a peroxynitrite (O=NOO-)–Cu(II) species. They show exogenous
phenol oxidative coupling or nitration, ignoring the possible role of Cu(I) in the process.
Copper(I) concentration in aqueous solutions is limited due to its disproportionation
reaction,
2Cu+
Cu2+
+ Cu0
(s)
K = 1×106
(aq)
(aq)
oxidations by oxygen from air to Cu(II) and low solubility of the hydroxide and halide salts [17].
The complex of Cu(I)-phenol stabilizes Cu+ and shifts the disproportionation reaction
(aq)
to the left increasing the Cu+(aq) concentration.
The complex of Cu(I)-phenol allows use of Cu2+(aq) ion as a source to the active Cu+ ion.
Cu2+(aq) is reduced by a piece of copper metal in deaerated solution containing phenol.
Similarily, Cu(I)(CH3CN)4 shifts the disproportionation reaction to the left increasing the
Cu+
concentration allowing a liquid-liquid two-phase system, with acetonitrile as a phase-
(aq)
transfer catalyst, in order to achieve electrophilic substitution in aromatic compounds not soluble
in aqueous solution.
EXPERIMENTAL
Reagents and solutions
All solutions were prepared from reagent grade chemicals or better. Distilled water was further
purified by passing through a Milli Q Millipore setup, with final resistivity of >10 MΩ/cm.
4

Apparatus and equipment
Deaerated system: The processes were carried out in strictly deaerated solutions using the
syringe technique with argon (UHP) gas. Photos of the system are presented in figure 3.
UV-Vis spectra: Spectra were recorded with a Varian-Cary 100 Bio UV-Vis Spectrophotometer.
The concentration of Cu2+
and indirectly Cu+ (after oxidation to Cu2+ with atmospheric
(aq)
dioxygen) was determined spectrophotometrically by the addition of ammonia to form the
2+
complex Cu(NH3)4 , which has a molar absorption coefficient of 60 M-1cm-1 at 604 nm.
Phase transfer system: The system was composed from a separating funnel equipped with a
mechanical stirrer with a gas trap and a pipe for feeding the inert gas into the solution. The
aqueous phase contains acetonitrile (1% v/v), divalent copper salt and HNO3 or H2SO4. The
reaction vessel further contains metal copper pipe. The reaction mixture was deaerated with
argon.
In the two phase process, the deaerated aqueous solutions contain Cu(II), metallic copper
and 1% v/v acetonitrile (which allowed formation of Cu(I)(CH3CN)4 by comproportionation)
and up to 1% nitric or sulfuric acid. The deaerated toluene serves as the organic phase; mixing
the phases allowed transfer of Cu(I) to the toluene phase and the selective ortho electrophilic
substitution.
HPLC: Organic starting materials and products were separated and identified with reverse phase
chromatography using a reversed phase 18 column and UV-Vis detector using the 270 nm
absorption band. A mixture of 50% acetonitrile (HPLC grade) and 50% 0.05M phosphate buffer
at pH=3.5 was used as the eluent at a rate of 1 mL/min. Calibrations for the starting material
(phenol) and for the main products (ortho/para nitrophenol, ortho/para phenosulfonic acid and
ortho/para nitrotoluene) using the same technique were performed.
Complex formation: Dissolving 0.02 gr CuSO4·5H2O in 80 ml aqueous 1 mM phenol solution,
deaerated with Ar and containing a coil of metal copper pipe (d = 4 mm, l = 150 mm) yields the
Cu(I) phenol complex after two hours at 30 C (while increasing the copper ion concentration to
2 mM (double the initial Cu(II) salt concentration). Flowing the copper ion concentration in the
solution exposed to air induced the percentage of Cu(I) formation in the deaerated solution.
5

Nitration of the complex Cu(I)-phenol: To the 80 ml deaerated solution after the complex
-
formation, 1 ml of concentrated nitric acid was added, resulting in 0.16M NO3 solution. The
reaction was monitored by HPLC and carried out in a temperature range of 25 to 65 C.
Quantum mechanical calculations: For quantum mechanical calculations we used the
Tecktronix CAChe system with the Zindo 3.0 program.
RESULTS AND DISCUSSION
We assume that the electrophilic substitution process, in the presence of Cu(I), involves two
stages, the first is the formation of the Cu(I) aromatic ring complex.
Figure 4 presents the change of the Cu(I) percentage of the total copper ion concentration
with time on reaction of Cu metal with Cu(II) in a deaerated solution containing phenol. The
concentration of the copper ions is doubled when all of the initial Cu(II) ions in the solution react
with metal copper forming two Cu(I) ions. Even with the stoichiometric molar ratio between
phenol and copper ion 1:1, more than 90% of the total copper ions are present as Cu(I) (figure 4).
In the second stage, on adding nitric acid to the first stage solution, a reaction takes place
yielding in the first hour at mild temperature (30 C) exclusively the ortho nitrophenol isomer,
with the para nitrophenol isomer appearing only after 60 minutes as corroborated by HPLC.
Figure 5 presents an HPLC chromatogram 40 mins after the start of the reaction and figure 6
presents kinetics of the two isomer concentrations. A reference experiment using the same
concentration of nitric acid, phenol and CuSO4 without the addition of copper metal, which
enables the formation of Cu(I) (the first stage), does not result in any reaction.
Lowering the temperature to 25 C causes a selective reaction but very slow one and after
60 minutes less than 1% of the phenol is reacted to yield 0.01 mM ortho nitrophenol compared to
0.2 mM (20%) at 30 C.
At higher temperatures the selectivity is compromised. Figure 7 presents HPLC
chromatograms 50 mins after the start of the reaction; the para nitrophenol isomer is present
(~30%) but most of the phenol (95%) reacted and converted to nitrophenol, ~70% of it to the
ortho isomer. The peak at 2.2 min can be attributed to oxidized product caused by traces of
molecular oxygen from air that penetrated into the sample despite the deaerated system.
Similar results were obtained when sulfuric acid was added to the system in the second
stage. Figure 8 presents the result of phenol sulfonation in the presence of Cu(I), which is 80%
6

more compared to the reference (without addition of copper metal in the first stage) under the
same conditions and 100% ortho compared to 70% ortho in the reference experiment.
A liquid-liquid two-phase system yields selective nitration of toluene (organic phase) to
ortho nitrotoluene compared to negligible reaction in a reference experiment (without
acetonitrile). The aqueous phase contains copper(II) sulphate, acetonitrile, 1% v/v, copper metal
and 1% HNO3.
Figure 9 presents a HPLC chromatogram of the aqueous phase of the liquid-liquid two-
phase system 12 h after mixing, showing only the ortho nitrotoluene isomer.
Discussion and Conclusions:
 The activity of phenol and toluene in the presence of copper(I) supports previous results
[1, 3] that show that the interaction between copper(I) and the aromatic ring resemble
exited states of the ring. Support for this assumption comes from a computational study
(Arrieta and Cossı'o) [5], which shows that loss of aromaticity and -electron
delocalization is the first step of the electrophilic aromatic nitration of phenol and in the
Ullmann reaction mechanism as suggested in a previous article [4].
 The selective ortho orientation of the substituted nitro group demonstrated by our
experimental results is supported by quantum mechanical calculations [2] that show
elongation of the ortho hydrogen carbon bond in the Cu(I)-phenol complex compared to
the native phenol and the other hydrogen-carbon bonds in the complex.
 Highly selective nitrations of phenol and toluene are accomplished under mild
conditions; the method can be easily exploited as an environmentally-friendly
commercial process.
 Copper(I) catalyzed sulfonation of phenol and toluene also proceed under mild conditions
similar to the nitration described above, which emphasize the role of Cu(I) as activator of
the aromatic compounds.
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7

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8

tpartsra laciGparG
9

Figure 1. Structure of phenol and Cu(I)-phenol complex from quantum mechanical calculation.
10

Figure 2. Possible electronic interaction between Cu(I) and phenol that resembles an exited state
of the ring due to back donation from Cu(I) to the * anti-bonding orbitals of the aromatic
system.
11

Figure 3. Photos of the system, A: syringe containing the reaction solution, copper metal,
magnetic stirrer and argon gas flow through the syringe; after 10 mins bubbling the solutions are
air free. B: The syringe (after deaeration) is sealed and stirred; when control temperature is
needed, the syringe is immersed in a controlled warming bath. Samples are taken from the 3-way
valve.
12

Figure 4. Percentage of monovalent copper of the total copper ion concentration (Cu+ and Cu2+)
against time, syringe containing: phenol 1 mM, initial concentration of CuSO4 1 mM, metal
copper, air free, T = 30 C.
13

Figure 5. HPLC chromatogram of a solution taken from a syringe 40 mins after introduction of
HNO3 0.16M, containing: phenol 1 mM, initial concentration of CuSO4 1 mM, Cu metal, air
free, T = 30 C.
14

0.25
0.2
Ortho-nitrophenol
Para-nitrophenol
0.15
0.1
mM
0.05
0
0
10
20
30
40
50
60
Time (min)
Figure 6. Kinetics of the reaction products after introduction of 0.16M HNO3, syringe
containing: phenol 1 mM, initial concentration of CuSO4 1 mM, Cu metal, air free, T = 30 C.
15

Figure 7. HPLC chromatogram of a solution taken from a syringe 30 min after introduction of
HNO3 0.16M, containing: phenol 1 mM, initial concentration of CuSO4 1 mM, Cu metal, air
free, T = 65 C.
16

Figure 8. HPLC chromatogram: a- commercial sulphophenol; b- phenol; c- after introduction of
H2SO4 to 1 mM phenol, 1 mM Cu+, metal copper in an Ar bubbled syringe.
17

Figure 9. HPLC chromatogram at 300 nm of the aqueous phase of a liquid-liquid two-phase
system, 12 h after mixing. Toluene as the organic phase and Cu(I) acetonitrile, 1% HNO3 in the
aqueous phase.
18