Mechanosynthesis of nitrosobenzenes: A proof-of-principle study in combining solvent-free synthesis with solvent-free separations

Article abstract of DOI:10.1039/c2gc35410a

Mechanochemical Oxone oxidation of selected para-substituted anilines was used as a rapid and solvent-free route to nitrosobenzenes; besides avoiding bulk solvents and short reaction times, this method exploits high vapour pressures of nitrosobenzenes for the solvent-free separation of the product by sublimation, demonstrating an entirely solvent-free route to chemical synthesis and product isolation. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2gc35410a

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Mechanosynthesis of nitrosobenzenes: a proof-of-principle study in
combining solvent-free synthesis with solvent-free separations†
Igor Huskić,a Ivan Halasz,*a Tomislav Friščićb and Hrvoj Vančika
Received 20th March 2012, Accepted 17th April 2012
DOI: 10.1039/c2gc35410a
particular, we demonstrate a mechanochemical methodology for
Mechanochemical Oxone oxidation of selected para-substi-
tuted anilines was used as a rapid and solvent-free route to
nitrosobenzenes; besides avoiding bulk solvents and short
reaction times, this method exploits high vapour pressures of
nitrosobenzenes for the solvent-free separation of the
product by sublimation, demonstrating an entirely solvent-
free route to chemical synthesis and product isolation.
the oxidation of anilines into nitrosobenzenes, accompanied by
solvent-free product isolation. Formation of the nitroso group
has been the missing step in methodologies for solvent-free
interconversions of nitrogen-based organic functionalities. The
high vapour pressures of nitrosobenzenes allow us to demon-
strate how solvent-free synthesis can be coupled with solvent-
free separation via sublimation.
Interest in mechanosynthesis has rapidly increased in the past
decade, through the realisation that mechanosynthesis is a
solvent-free‡ and low-energy pathway1 to organic molecules,2
pharmaceutical materials and materials based on coordination
bonds (e.g. metallodrugs, metallopharmaceuticals and porous
metal–organic frameworks, MOFs).3 Mechanochemistry has
been used with great success for organic coupling reactions and
condensations, including imine condensations,4 [2 + 3] click
coupling;5a Diels–Alder cycloadditions,5b Michael additions,5c,d
Wittig reactions,5e Morita–Baylis–Hillman reactions5f as well as
palladium-catalyzed Suzuki6a and Sonogashira reactions.6b,c
Remarkable results have been obtained by applying mechano-
chemistry to organocatalytic reactions, especially in asymmetric
catalysis7a,b and [2 + 2] photocyloadditions.7c Despite numerous
successes, there are two principal obstacles to establish mechan-
ochemistry as a viable alternative to solution-based synthesis.
Firstly, the development of methods for functional group inter-
conversion,8 which is the basis for systematic organic chemistry,
has so far not been adequately addressed. Secondly, whereas a
number of mechanochemical reactions proceed in quantitative
yields and their products can be structurally analysed via com-
pletely solvent-free routines (e.g. using powder X-ray diffrac-
tion),9 organic reactions often require post-synthetic solvent-
based purification steps, thus diminishing the value of solvent-
free synthesis.
It was previously demonstrated that anilines can be selectively
oxidised, in a mechanochemical process using a planetary mill,
to symmetrically substituted azoxybenzenes, azobenzenes or
nitro compounds using a wide range of oxidising agents.8a
These functional group interconversions generally involve the
formation of a nitrosobenzene intermediate (Scheme 1a) which
rapidly reacts with a hydroxylamine intermediate or an amine to
give an azoxybenzene or an azobenzene, respectively
(Scheme 1b). Alternatively, further oxidation of the nitroso com-
pound yields the nitro compound. Conversions of other nitrogen
functionalities (e.g. nitriles,10 nitrones,11 imines,2a,b oximes12
and nitro13 compounds) were also conducted either mechano-
chemically or using microwave-assisted solid-state routes,
We now present a proof-of-principle study which addresses
these two major problems of milling mechanochemistry. In
aDepartment of Chemistry, Faculty of Science, University of Zagreb,
Horvatovac 102a, HR-10002 Zagreb, Croatia. E-mail: ihalasz@chem.
pmf.hr; Fax: +385 1 460 6401; Tel: +385 1 460 6416
bDepartment of Chemistry, McGill University, 801 Sherbrooke St. W.,
H3A 0B8 Montreal, Canada
†Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra of products of mechanochemical synthesis before and after
sublimation. Example thermogravimetric isothermal curve for p-bromo-
nitrosobenzene demonstrating the ease of sublimation and detailed
experimental results. See DOI: 10.1039/c2gc35410a
Scheme 1 (a) Oxidation and reduction reactions from anilines to nitro-
benzenes and back. Oxidation reactions are denoted with [O], reduction
with [R]. (b) Coupling of nitrosobenzene with amine to yield azoben-
zene and with hydroxylamine to yield azoxybenzene.
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leaving the operations that generate the nitroso group or use it as
a starting point as a missing link in the system of solvent-free
conversions of nitrogen-based functionalities. At the same time,
high reactivity and ease of oxidation make nitrosobenzenes
difficult targets in traditional solution-based synthetic chemistry,
with typical yields around 70%. In condensed phases (solution,
solid) nitrosobenzenes rapidly undergo reversible dimerisation to
form azodioxides.14 However, the high reactivity of nitrosoben-
zenes has made them useful reagents in materials chemistry,
most notably as precursors in the synthesis of photoactive non-
symmetrical azobenzenes15 and, very recently, as active sites in
MOFs capable of covalently trapping small molecules.16
Considering the formation of nitrosobenzenes as intermediates
during mechanochemical oxidation of anilines,8a and knowing
that nitrosobenzenes can be readily purified by sublimation,14 we
decided to investigate if the synthesis and isolation of nitroso-
benzenes could be accomplished in a selective and solvent-free
procedure. We were inspired by the report of Priewisch and
Rück-Braun17 describing an efficient synthesis of nitrosoben-
zenes in a biphasic system that used Oxone18 as the oxidant in
dichloromethane.
Our exploration of the solvent-free mechanosynthesis of nitro-
sobenzenes is based on a limited set of differently substituted
model molecules. While the yields resulting from our method-
ology are comparable to those in biphasic reaction systems, our
methodology avoids bulk solvents, provides crude products in
one short step and enables their solvent-free purification by sub-
limation. As model reactants, we have used p-iodoaniline, p-bro-
moaniline, p-chloroaniline, p-nitroaniline and p-methylaniline
that were previously obtained in our laboratory through solution
routes19 (Scheme 1a). As the oxidising agent, potassium hydro-
genperoxosulphate8a,10 (commercially available as Oxone) was
employed. Formation of the nitrosobenzene in a mechanochem-
ical reaction was confirmed by extracting the mixture after grind-
ing with chloroform (CDCl3), collecting 1H and 13C NMR
spectra (Fig. 1a, also see ESI†) and comparing them to those of
standard samples prepared by solution methods.19 With all ani-
lines tested, the corresponding nitrobenzene also formed, and all
reactions, except that with p-iodoaniline, also produced the azox-
ybenzene as a by-product (Fig. 1a). Since nitrosobenzenes
exhibit high vapour pressures, the crude mixtures were sublimed
under reduced pressure to isolate the product (Fig. 2).
The entire procedure of nitrosobenzene preparation can thus
be accomplished in a solvent-free manner. The only impurity
found after sublimation was, as revealed by solution H NMR
spectroscopy, the corresponding nitrobenzene (Fig. 1b). This,
however, is a very satisfactory outcome as the purification of
nitrosobenzenes often presents difficulties due to their instabil-
ity.17 Indeed, if nitrosobenzene synthesis is directed, as is often
the case, towards making a precursor for non-symmetrical azo-
1
Fig. 1 Segments of example NMR spectra (CDCl3) for the mechano-
chemical nitrosobenzene synthesis: (a) product of p-bromoaniline oxi-
dation after milling and (b) after sublimation. (c) Fourier-transform
infrared spectrum of dimeric p-bromonitrosobenzene product, highlight-
ing the characteristic band of the azodioxy group.14
benzene, the presence of
a nitrobenzene would not be
relevant.17,19
substantially improved upon addition of equimolar amount of
NaHCO3 in the reaction mixture as compared to neat grinding
(Table 2). For instance, for p-Br the yield increased five-fold
while it increased seven to eight times for p-I. This may be
explained by NaHCO3 acting as a base to neutralise acidic
species formed during oxidation, so as to prevent the acid-cata-
lysed reactivity between nitrosobenzene and hydroxylamine or
amine.
Compounds listed in Table 1 were, except for the p-NO2 sub-
stituent, obtained in yields above 50% (and up to 85% for the p-
I substituent). Comparing our solid-state route with the solution
approach, p-Br was obtained in higher yield and comparable
purity (Table 1). Formation of p-NO2 was slowest and the yield
could be increased by longer grinding, although at the expense
of purity. We found that both purity and yield could be
1598 | Green Chem., 2012, 14, 1597–1600
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previously been reported to improve reactivity in other reaction
systems,3a,9 introducing a liquid phase in our case reduced both
the purity and the yield of nitrosobenzenes (see ESI†). Mechano-
chemical nitrosobenzene synthesis under LAG conditions was
more successful with aprotic and non-polar liquids, suggesting
that protic liquid phases facilitate the formation of azobenzene or
azoxybenzene.
In summary, we have demonstrated a rapid and selective
solvent-free synthesis of nitrosobenzenes under mechanochem-
ical conditions. The reported strategy complements existing
approaches for the solvent-free interconversions of nitrogen
functionalities, such that mechanochemical treatment of anilines
with a range of oxidising agents can now be selectively directed
to a variety of products, including nitrosobenzenes, azoxyben-
zenes, azobenzenes or nitrobenzenes.
Our results complement the work on Oxone oxidation of ani-
lines by Stolle’s group,8a who used acidic inorganic auxiliaries
to direct the formation of azobenzenes and azoxybenzenes.
Specifically we demonstrate that weakly basic inorganic auxili-
aries facilitate the formation of the nitrosobenzenes under similar
conditions. We are currently trying to develop mechanochemical
approaches to asymmetric azobenzenes and azoxybenzenes, as
well as solvent-free routes to nitrosobenzenes bearing protic
(phenol, carboxylic acid) functionalities.
Fig. 2 Separation of the nitrosobenzene product by sublimation follow-
ing mechanochemical synthesis, illustrated in case of p-iodonitrosoben-
zene: the green monomeric nitrosobenzene is collected on the cold
finger.
Table 1 Results of nitrosobenzene syntheses by mechanochemical
Oxone oxidation of anilines. The only impurity found following
sublimation was the corresponding nitrobenzene
Substituent
p-I
p-Brc
p-Cl
p-NO2
p-Me
Yielda/%
85
92
20
Yes
80 (70)
90 (95)
20
70
80
20
Yes
26
90
30
No
52
69
20
Yes
Purityb/%
Experimental section
Milling time/min
NaHCO3 addition
Mechanochemical synthesis of the para-substituted nitrosoben-
Yes
zenes was conducted by placing stoichiometric amounts of the
a Yield is calculated only for the nitrosobenzene taking into account the
mixture composition after sublimation. b Purity is reported as the molar
corresponding aniline (0.25 mmol) and Oxone® (K2SO5
×
K2SO4 × KHSO4, 0.50 mmol) in a custom made stainless steel
jar with two 7 mm stainless steel balls which was then milled at
a frequency of 25 Hz for variable amount of time (5 to
40 minutes) on a Retsch MM 200 ball mill. Neat and liquid
assisted grinding were employed in the optimization of reaction
conditions, as was grinding with NaHCO3 (∼1.0 mmol) to neu-
tralise potassium hydrogensulphate and other acidic species. The
nitrosobenzene was separated from the mixture by sublimation
under reduced pressure (∼0.1 mbar) during which some of the
nitro side-product also sublimed. An aluminium foil cylinder
was placed over the cold finger to ensure easier and complete
collection of the sublimation product.
fraction of nitrosobenzene in
a mixture with the corresponding
nitrobenzene obtained after sublimation, determined by 1H NMR.
c Numbers in brackets relate to solution synthesis.15
Table 2 Comparison of reaction yields (in %) and purities (in %, in
brackets) of neat mechanochemical syntheses of nitrosobenzenes with
and without added NaHCO3
NaHCO3
p-I
p-Br
p-Cl
Yes
No
85 (92)
∼12 (∼80)
80 (90)
∼15 (∼60)
70 (80)
∼8 (∼65)
Acknowledgements
The successful application of mechanochemical Oxone
milling for the synthesis of the halo- or methyl-substituted nitro-
sobenzenes led us to explore the reactivity of p-aminophenol
and p-aminobenzoic acid. Attempted oxidations of p-OH and
p-COOH anilines did not yield the corresponding nitrosoben-
zenes, but resulted in the formation of non-characterised tars.
This is most likely due to the more acidic environment which
can catalyse the formation of azobenzenes and azoxybenzenes.
Grinding with an excess of NaHCO3, in an attempt to neutralise
the mixture, also did not result in the formation of
nitrosobenzenes.
This work was supported by the Ministry of Science, Education
and Sport of the Republic of Croatia (Grant No. 119-1191342-
1334). We are grateful to Mr Boris Milić for the grinding jars
and to Dr Ivica Ðilović for critical discussions. T.F. acknowl-
edges the support of McGill University and the FQRNT Centre
for Green Chemistry and Catalysis.
Notes and references
‡The term “solvent-free” is used here to denote the avoidance of bulk
external solvent. In cases when the nitrobenzene as the principal bypro-
duct of the nitrosobenzene synthesis is liquid, the reactions cannot be
mechanistically considered to be truly “solvent-free”. This is true in a
number of mechanochemical syntheses, including those of certain
We have also explored the synthesis using the liquid-assisted
grinding (LAG) technique with protic polar solvents, as well as
either protic or aprotic non-polar solvents. Although LAG has
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