New "green" approaches to the synthesis of pyrazole derivatives

Article abstract of DOI:10.3390/12071482

A novel approach to the synthesis of pyrazole derivatives from tosylhydrazones of α,β-unsaturated carbonyl compounds possessing a β-hydrogen is proposed, exploiting microwave (MW) activation coupled with solvent free reaction conditions. The cycloaddition was studied on three ketones (trans-4-phenyl-3-buten-2-one, β-ionone and trans-chalcone). The corresponding 3,5-disubstitued-1H-pyrazoles were obtained in high yields and after short reaction times. In order to simplify and point out the green chemistry features of the method, a further improvement was achieved under the same catalytic conditions with a "one pot" synthesis of these heterocyclic compounds, starting directly from their carbonyl precursors via tosylhydrazones generated in situ. For an exhaustive study, the dielectric properties of the solid reaction mixtures were also measured, in order to obtain input data for the numerical simulation of their heating behaviour in the single mode MW cavity which was used for experimental work. In order to supply a valid methodology and tool for measuring the environmental impact, a comparative study between the synthetic route proposed and the classical synthetic route has been carried out.

Full text of DOI:10.3390/12071482

Molecules 2007, 12, 1482-1495
molecules
ISSN 1420-3049
© 2007 by MDPI
www.mdpi.org/molecules
Full Paper
New “Green” Approaches to the Synthesis of Pyrazole
Derivatives
Anna Corradi 1, Cristina Leonelli 1, Antonino Rizzuti 1, Roberto Rosa 1,*, Paolo Veronesi 1,
Romano Grandi 2, Sara Baldassari 3 and Carla Villa 3
1
Dipartimento di Ingegneria dei Materiali e dell’Ambiente, Università degli Studi di Modena e
Reggio Emilia, Via Vignolese, 905, 41100 Modena, Italy. FAX: +390592056243;
tel: +390592056247; e-mails: corradi.anna@unimore.it, leonelli@unimore.it,
rizzuti.antonino@unimore.it, paolov@unimore.it
2
Dipartimento di Chimica, Università degli Studi di Modena e Reggio Emilia, Via Campi, 183, 41100
Modena, Italy; e-mail: romano@unimore.it
3
Dipartimento di Scienze Farmaceutiche dell’Università degli Studi di Genova, Viale Benedetto XV,
3, 16132 Genova, Italy; e-mails: s.baldassari@unige.it, carlavilla@unige.it
* Author to whom correspondence should be addressed; e-mail: rosa.roberto@unimore.it
Received: 31 May 2007; in revised form: 16 July 2007 / Accepted: 16 July 2007 / Published: 19 July
2007
Abstract: A novel approach to the synthesis of pyrazole derivatives from tosylhydrazones
of α,β-unsaturated carbonyl compounds possessing a β-hydrogen is proposed, exploiting
microwave (MW) activation coupled with solvent free reaction conditions. The
cycloaddition was studied on three ketones (trans-4-phenyl-3-buten-2-one, β-ionone and
trans-chalcone). The corresponding 3,5-disubstitued-1H-pyrazoles were obtained in high
yields and after short reaction times. In order to simplify and point out the green chemistry
features of the method, a further improvement was achieved under the same catalytic
conditions with a “one pot” synthesis of these heterocyclic compounds, starting directly
from their carbonyl precursors via tosylhydrazones generated in situ. For an exhaustive
study, the dielectric properties of the solid reaction mixtures were also measured, in order
to obtain input data for the numerical simulation of their heating behaviour in the single
mode MW cavity which was used for experimental work. In order to supply a valid
methodology and tool for measuring the environmental impact, a comparative study
between the synthetic route proposed and the classical synthetic route has been carried out.

Molecules 2007, 12
Keywords: Pyrazole derivatives, solvent free cycloaddition, microwaves.
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Introduction
Microwave (MW) irradiation has been widely exploited in the last decades to carry out a striking
number of organic syntheses, benefiting from the dielectric heating in terms of reduced reaction times
and increased yields, especially when coupled with solvent-free techniques. Generally three types of
solvent-free procedures can be coupled with dielectric heating provided by a microwave source:
reactions among neat reagents, reactions among supported reagents on mineral solid supports and
phase transfer catalysis reactions. The neat reagents procedure is doubtlessly the most pursued one
due, above all, to its easy work-up and negligible use of solvents for purification/separation stages.
One of the most fertile applications in this field, also known as Microwave Assisted Organic Syntheses
(MAOS) technique, is heterocyclic chemistry, as reported in a recent review [1]. In particular, the
synthetic pathways of pyrazole derivatives represent an interesting topic since these compounds have
numerous applications in the pharmaceutical and agrochemical industry [2].
Some of the most widespread synthetic strategies to obtain these heterocyclic structures are the
reaction between hydrazines with β-difunctional compounds [3] and 1,3-dipolar cycloaddition of diazo
compounds onto multiple bonds [4]. This last approach, which requires the preparation and the
handling of the toxic and potentially explosive diazo compounds, is of secondary importance.
Aggarwal et al. have reported [5] a method that represents a safe alternative for handling diazo
compounds. This approach is based on the Bamford-Stevens reaction and uses tosylhydrazone salts as
diazo precursors. They found that tosylhydrazone salts can be cleanly converted to diazo compounds
under mild reaction conditions and in a wide range of solvents. These diazo compounds can then be
induced to react directly with alkenes or alkynes to synthesize pyrazoles after additional steps.
Bamford and Stevens first reported in 1952 the base mediated decomposition of substituted
arylhydrazones to form diazo compounds [6]. A few diazo compounds could be isolated if mild
temperatures were employed, but in most cases, the diazo compounds decomposed thermally to form
alkenes as a result of loss of dinitrogen followed by a 1,2-hydrogen shift. Another synthetic route
towards pyrazole derivatives, first demosntrated by Hart and Brewbaker, consists of an intramolecular
cycloaddition of 3-diazoalkenes generated from the corresponding ethyl alkenylnitrosocarbamates [7].
Doyle et al. [8] observed formation of pyrazoles during reaction of the corresponding tosylhydrazone
salt with Rh2(OAc)4. A one-pot synthesis of 3(5)-substituted-1H-pyrazoles from aldehydes and
diethoxyphosphorylacetaldehyde tosylhydrazone is also described in the literature [9]. Another one-pot
approach has been proposed by Aggarwal et al., using diazo compounds generated in situ from
tosylhydrazone salts [2]. They studied two different routes to pyrazoles: first, direct 1,3-cycloaddition
of diazo compounds onto alkynes, and second, employing an olefin bearing a leaving group, which
would afford the pyrazole after an elimination/aromatization of the cycloadduct intermediate.
Moreover Grandi et al. [10] demonstrated that tosylhydrazones of some acyclic α,β-unsaturated
carbonyl compounds containing an hydrogen atom in β position, on treatment with NaBH4 or CH3ONa
or K2CO3 in alcoholic solvents (such as CH3OH) can lead to an intramolecular 1,3-dipolar
cycloaddition to give pyrazole derivatives (Scheme 1).

Molecules 2007, 12
Scheme 1. Reaction mechanism for intramolecular 1,3-dipolar cycloaddition of
1484
tosylhydrazones derived from acyclic α,β-unsaturated carbonyl compounds with a β−
hydrogen.
N
N
N
N
N SO2Ar
B
NHSO2Ar
H
N
N
N
H
N
Results and Discussion
Synthesis
On the basis of these studies in the present work we report simple and mild solvent-free microwave
mediated methodologies for the synthesis of pyrazoles derivatives from α,β-unsaturated carbonyl
compounds.
Table 1. Physical and chemical properties of products a-c obtained under microwave activation.
R'
3
N
H
4
N
H
5
R
a-c
bp, °C b
(mmHg)
1H-NMR data,
Compound
a
R
R’
mp, °C a
δ/ppm
2.31 (3H, s, CH3C(3)),
6.35 (1H, s, C(4)H),
7.30-7.75 (5H, aromatic)
C6H5
CH3
124-126*
-
CH3
C
H3C
0.95 (6H, s, (CH3)2C),
1.42 (3H, s, CH3C=C),
2.31 (3H, s, CH3C(3)),
5.80 (1H, s, C(4)H)
165-170
(0.1)
b
c
CH3
-
CH3
6.85 (1H, s, C(4)H),
7.32-7.74 (10H,
aromatic)
C6H5
C6H5
200-202**
-
*Crystallization solvent = 96% ethanol; **crystallization solvent = cyclohexane.
a Mp reported in the literature for compound a: 125-126 °C [10]; for compound c: 200 °C [11].
b Bp reported in the literature for compound b: 148-150 °C (0.01 mmHg) [10].

Molecules 2007, 12
1485
We investigated in detail three carbonyl substrates: trans-4-phenyl-3-buten-2-one, β-ionone and
trans-chalcone. Compounds a-c (Table 1) have been obtained under microwave activation following
two methodologies (MW1 and MW2).
The first approach to synthesize the pyrazole derivatives (MW1) refers to the 1,3-cycloaddition of
the corresponding tosylhydrazones of the carbonyl compounds selected, using a base in dry media
(Scheme 2). Tosylhydrazones were prepared following the classical procedure (ketone plus
tosylhydrazine in methanol at reflux) [12].
Scheme 2. Reaction scheme for the synthesis of pyrazoles a-c from tosylhydrazones.
R'
O
R'
H
H
N
H
R
N N S
N
O
H
H
R
a-c
To fine-tune the method, and using the synthesis of compound a from the tosylhydrazone of trans-
4-phenyl-3-buten-2-one as a model reaction, several experiments were carried out under microwave
activation using a base impregnated on mineral solid supports, a neat base in the reaction mixture, a
base with an energy transfer agent such as N,N-dimethylformamide or graphite. The most remarkable
results are reported in Table 2.
Table 2. Operative conditions and relative yields for the synthesis of product a from tosylhydrazone.
CH3
N
H
N
H
a
Time,
min.
45
Temp.,
°C
Entry
Method
Yield, %
A
B
C
D
E
F
K2CO3 (8:1)*
K2CO3/KOH (1/1:1)*
KF/Al2O3 (1/1:1)*
K2CO3 (4:1)* + ETI1
K2CO3 (4:1)* + ETI2
K2CO3 (2:1)* + ETI2
150
n.r.
84
65**
62**
95
45
145
10
145
10
150
1
130
1
130
95
* Molar ratio
ETI1 = Energy transfer improver: powdered graphite (catalytic amount)
ETI2 = Energy transfer improver: DMF (catalytic amount)
**Remainder = degradation compounds

Molecules 2007, 12
1486
In general, the simple mixing of neat reagents gave better results than mineral solid supports in
terms of reaction times and yields. Only the use of K2CO3 as a base, without any energy transfer
improver, did not lead to any product. The addition of an energy transfer improver enhanced the
reaction speed and yields and allowed us to reduce both the reaction temperature and amount of the
base. The best performing conditions resulted from neat reagents in the presence of anhydrous K2CO3
(substrate/base 1:2) and a catalytic amount of N,N-dimethylformamide (DMF) as an energy transfer
improver [13]. Figure 1 shows the temperature and power profiles corresponding to entry F in Table 2
for the MW1 synthetic protocol of product a. This method was then applied to the synthesis of all
compounds. The results are reported in Table 3.
Figure 1. Graph of temperature and power % vs time for the synthesis of pyrazole a
following MW1 synthetic approach under the entry F (Table 2) operative conditions.
160
Temperature
140
120
100
80
Power
60
40
20
0
0
10
20
30
40
50
60
70
Time (s)
In order to evaluate how microwave irradiation can affect cyclization, the best performing method
(entry F) was also carried out under conventional heating (thermostated oil bath) under the same
conditions in terms of reagents quantities and reaction vessel, in order to obtain compound a.
Moreover, due to the slower temperature increase of conventional heating, reaction time was
considered starting from when the temperature setpoint (130 °C) was reached. No product was
detected after one minute of conventional treatment at 130 °C. When conventional heating was
extended TLC monitoring of the oil bath reaction mixture revealed that the substrate started reacting
only after 10 minutes, but then some degradation compounds were also detected.
In the second phase of the work (MW2), as a further improvement and simplification, a “one-pot”
approach to the synthesis of the desired heterocyclic products was investigated, removing the
tosylhydrazone formation step. Hence, starting directly from the carbonyl precursors (Scheme 3) and
using the catalytic conditions which gave the best results in the previous approach (entry F =
K2CO3/substrate 2:1, 130 °C, DMF as energy transfer improver), the synthesis of the pyrazole
derivatives a-c was studied at different reaction times, monitoring the product formation by TLC. The
results obtained from this last synthetic pathway are reported in Table 4. As an example, Figure 2
shows the temperature and power profiles for MW2 synthetic protocol of product a.

Molecules 2007, 12
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Table 3. Solvent free microwave-mediated synthesis (MW1) of compounds a-c under the
best catalytic conditions (entry F – Table 2) from tosylhydrazones.
Compound
Starting substrate
Time, min. Yield, %
O
H3C
H
N
S
C
N
H
C
C
O
a
1
3
95
88
H
O
H3C
H
N
N
S
C
H
C
C
H
b
c
O
O
H
N
N
S
C
H
3
65
C
C
O
H
Scheme 3. Reaction scheme for the synthesis of pyrazoles a-c starting directly from
carbonyl precursors.
R'
N
H
R'
R'
H
H2NNHTs, K2CO3
MW,130 °C
H
R
N N Ts
H
R
O
N
H
H
H
R
a-c
Table 4. MW-assisted “one pot synthesis” (MW2) of compounds a-c from carbonyl precursors.
Time,
min.
Yield,
%
Product
a
Starting substrate
H3C
O
H
C
H
C
3
95
H3C
O
H
C
C
H
b
c
5
5
84
65
O
H
C
C
H

Molecules 2007, 12
Figure 2. Graph of temperature and power % vs time for the synthesis of pyrazole a
1488
following MW2 synthetic approach under the entry F (Table 2) operative conditions.
140
120
Temperature
Power
100
80
60
40
20
0
0
20
40
60
80
100
120
140
160
180
200
Time (s)
With a simple mixing of the reagents (ketone, tosylhydrazide, K2CO3 and DMF) and with a
maximum reaction time of five minutes all the compounds were obtained in good yields, very close to
those obtained using the best catalytic conditions of MW1 (Yield % entry F: MW1/one pot: compound
a = 95/95, compound b = 88/84, compound c = 65/65).
Again, in order to evaluate how microwave irradiation affected the cyclization, the “one pot”
synthesis of compound a was also carried out under conventional heating (thermostated oil bath) under
the same conditions in terms of reagents quantities and reaction vessel used. No product was detected
after 3 minutes of treatment at 130 °C. The reaction in oil bath was also monitored for longer reaction
times and after 10 minutes of treatment at 130 °C some degradation products were detected.
Modelling
The software Concerto 4.0 (Vector Fields, U.K.) has been used to numerically simulate the heating
behaviour of the reactants mixture in the MW single mode applicator. The numerical simulation
helped explaining the different yields and cleanness measured when using different reactants in the
same experimental conditions.
The study of microwave heating of the reactants was conducted only for the MW-assisted one pot
synthesis of products a-c (Table 3). The use of the Concerto software allowed us to determine the SAR
(Specific Absorption Rate, in W/kg), and thus to describe how heat is generated within the reaction
vessel. The calculated SAR in the mid horizontal section of the reaction vessel is reported in the
thermal plots shown in Figure 3, as a function of compounds a-c.

Molecules 2007, 12
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Figure 3. SAR in the mid section of the reaction vessel centrally positioned in the single
mode applicator (300W forward power).
The SAR distribution shows non-homogenous heating in the case of stationary load (power
generation higher in the right side of the load), which, however, can be compensated by stirring. This
distribution is due to the presence of the load inside the cavity, which is not equipped with plungers or
movable short circuits to alter the electric field distribution. As a matter of fact, the load perturbs the
empty cavity electric field distribution, having the maximum intensity region move away from the
centre of the sample. This unwanted effect, on the other side, results useful in case of sample stirring
(rotation), since it allows a much higher homogeneity of power generation with respect to a
configuration in which the maximum of the electric field would be in the exact centre of the load.
Modeling results show also that the solid reaction mixture for product a synthesis presents a 30%
lower power generation in the examined section. However, it was experimentally observed that this
particular sample (a) is the one that lead to the cleanest products and higher yield reaction. This
behaviour could be ascribed to the easier and more accurate temperature control of the reaction in the
case of lower power generation by the reactants (temperature gradients are reduced). On the other
hand, in this case the overall process energy efficiency is lower, suggesting that an improved stirring
and homogenisation could lead to higher yields for products b and c as well provided the synthesis
conditions can be effectively controlled, minimising localised over- or under- heating.
Green metrics evaluation
A comparative quantitative assessment of the “greenness” of the new processes here proposed, in
comparison to the classical one [10], was conducted with a rational approach of the chemical
sustainability of a reaction (“Green metrics”). For this the “Environmental Assessment Tool for
Organic Syntheses” software (EATOS) was used [14, 15]. This software, which takes into account the
mass economy as well as the environmental and human health impact of the materials involved, has
been applied to assess the eco-sustainability of the competing processes. EATOS elaborates all data
relative to all materials used in the process (reagents, solvents, auxiliary materials, products and
secondary products) and supplies an evaluation histogram. It is also possible to compare two or more
chemical processes placing side by side their histograms and standardizing the quantities. As an
example, in Figure 4 the histograms related to the environmental impact of the synthesis of compound
a using both the conventional route in methanol [10], and the newly proposed microwave approaches

Molecules 2007, 12
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are reported. As the order of magnitude of the environmental impact of the classic procedure is much
higher, the green metrics relative to MW1 and MW2 processes are also shown in detail in Figure 5.
Figure 4. Evaluation histograms of classic versus MW-mediated solvent-free approaches,
MW1 and MW2 (one pot), for the synthesis of compound a. S-1= inverse selectivity (or
mass index). E = environmental factor. EIin and EIout represent respectively S-1 and E
weighted in function of the “weighting factors”: costs, risk, human toxicity, eco-
toxicology. PEI represents Possible Environmental Impact.
Figure 5. Evaluation histograms of MW mediated solvent-free approaches, MW1 and
MW2 (one pot), for the synthesis of compound a. S-1= inverse selectivity (or mass index).
E = environmental factor. EIin and EIout represent respectively S-1 and E weighted in
function of the “weighting factors” (costs, risk, human toxicity, ecotoxicology). PEI
represents Possible Environmental Impact.

Molecules 2007, 12
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The graphical results shown in Figure 4 suggest that the performance indicators of our innovative
methods are considerably improved from a green chemistry point of view. A further confirmation can
be given by the rapidity of the process which is not considered by EATOS but which is important in a
green chemistry procedure context in terms of reduction of energy consumption.
Conclusions
The good results obtained in terms of reaction speed and yields with the proposed microwave-
mediated solvent-free processes indicate that these procedures can be considered simple, fast and eco-
friendly synthetic pathways to obtain pyrazole derivatives from α,β-unsaturated ketones with a β-
hydrogen. This is confirmed by the EATOS software, especially with regards to the new “one-pot”
method. On equal terms of yield and quite similar reaction times, this last approach has to be
considered the best synthetic route taking into account atom economy, step reduction and further
methanol elimination in the synthesis of tosylhydrazones, in full agreement with the Green Chemistry
principles.
Experimental
General
trans-4-Phenyl-3-buten-2-one (≥99%), β-ionone (96%), trans-chalcone (97%), p-toluenesulfonyl-
hydrazide (~99%), K2CO3, KF, Al2O3, KOH and graphite flakes were provided by Sigma-Aldrich
(Milan, Italy). N,N-dimethylformamide and diethyl ether were provided by Merck (Darmstadt,
Germany). MW irradiation was supplied, for all samples, by a commercial SynthewaveTM 402 –
Prolabo monomode reactor specifically designed for organic synthesis. This reactor operates at 2.45
GHz of frequency with a maximum output power of 300 W. The temperature measurement is supplied
by an IR thermometer pointed to the external wall of the reaction vessel. The instrument’s software is
able to continuously varying the output power as a function of the temperature detected. A more
rigorous measurement of the load local temperature was obtained using one or more optical fibers
(Neoptix Reflex, 4 channels) introduced into the bulk reaction. Homogenous mechanical stirring of the
solid samples was obtained thanks to a curved Pyrex rod fixed on the top of the cavity while the
reaction vessel continuously rotates at 60 rpm. IR spectra were acquired with a Bruker Vertex 70 FT-
1
IR spectrometer provided with an ATR cell. H-NMR spectra were recorded on a Bruker Advance
DPX instrument (400 MHz) with TMS as an internal standard; chemical shifts are reported as δ (ppm)
relative to TMS. Elemental analyses were performed on CE Instruments – EA 1110 CHNS-O. Melting
and boiling points were determined on a Büchi 510 apparatus and are uncorrected. Oil bath
temperature measurements were carried out using a Comark digital thermometer.
Microwave mediated synthesis of pyrazoles a-c (MW1). General procedure
In a 40 mL Pyrex tube, the appropriate tosylhydrazone of the studied carbonyl compounds (10
mmol), previously prepared by a classical procedure [12], was mixed together with anhydrous K2CO3

Molecules 2007, 12
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(20 mmol). A minimum amount of N,N-dimethylformamide (30 mg/mmol of organic substrate) was
added in order to improve energy transfer [13]. The reaction mixture was placed in the microwave
cavity and irradiated under stirring at 130 °C for an appropriate time (as reported in Table 2),
maintaining this temperature by power modulation from 5 to 300 W. The product formation was
monitored during all the processes by TLC (silica gel plates with fluorescent indicator, diethyl ether/
petroleum ether 9:1 as mobile phase). After cooling to room temperature, the organic product was
recovered by elution with diethyl ether (50 mL) and filtration on a Gooch filter. The solution was
evaporated under reduced pressure and the crude product was purified by recrystallization with the
appropriate solvent or by bulb-to-bulb distillation under vacuum.
Synthesis of pyrazole a from tosylhydrazone under conventional heating. General Procedure
In a 40 mL Pyrex tube, tosylhydrazone of trans-4-phenyl-3-buten-2-one (10 mmol), previously
prepared by a classical procedure [12], was mixed together with anhydrous K2CO3 (20 mmol). A
minimum amount of N,N-dimethylformamide (30 mg/mmol of organic substrate) was added (as in
microwave procedure) [13]. The reaction mixture was heated under stirring by a thermostated oil bath
settled at 130 °C. Reaction time was considered when the reaction bulk reached this temperature.
Product formation was monitored by TLC (silica gel plates with fluorescent indicator, diethyl ether/
petroleum ether 9:1 as mobile phase).
Microwave-mediated “one-pot synthesis” of pyrazoles a-c (MW2). General procedure
In a 40 mL Pyrex tube, the appropriate α,β-unsaturated ketone (10 mmol) was mixed in the
reaction vessel with a stoichiometric amount of p-toluenesulfonhydrazide. After a gentle stirring 20
mmol of K2CO3 and a minimum amount of N,N-dimethylformamide (30 mg/mmol of organic
substrate) were added. The reaction mixture was placed in the microwave cavity and irradiated under
stirring at 130 °C for the appropriate time (as reported in Table 3), maintaining this temperature by
power modulation from 5 to 300 W. The product formation was monitored by TLC in the same
conditions of the MW1 method. After cooling to room temperature, the organic product was recovered
as described in the previous procedure.
“One pot” synthesis of compound a under conventional heating. General Procedure
In a 40 mL Pyrex tube, 10 mmol of trans-4-phenyl-3-buten-2-one was mixed in the reaction vessel
with a stoichiometric amount of p-toluenesulfonhydrazide. After a gentle stirring 20 mmol of K2CO3
and a minimum amount of N,N-dimethylformamide (30 mg/mmol of organic substrate) were added.
The reaction mixture was heated under stirring by a thermostated oil bath settled at 130 °C. Reaction
time was considered when the reaction bulk reached this temperature. Product formation was
monitored by TLC (silica gel plates with fluorescent indicator, diethyl ether/ petroleum ether 9:1 as
mobile phase).

Molecules 2007, 12
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Modelling
During microwave irradiation, the presence of the reaction vessel within the monomode cavity
deeply influences the heating behaviour and the energy efficiency of the whole process, modifying the
electromagnetic field distribution. The model used to better evaluate the heating process was chosen so
as to represent the inner metal structure of the SynthewaveTM 402 single mode applicator as shown in
Figure 6.
Figure 6. Microwave cavity of the Prolabo SynthewaveTM 402.
It is composed of a rectangular metallic enclosure (microwave applicator) containing in the central
position a 24 mm diameter vessel made of Pyrex glass, thickness 2 mm, filled up to 20 mm height with
the load (the three different solid reaction mixtures for one pot syntheses of product a-c), whose
dielectric properties were measured at room temperature in the 1-3 GHz frequency range by an Agilent
85070E Dielectric Probe Kit connected to a vector network analyser. On one side of the applicator is
positioned a port excited sinusoidally in the fundamental TE10 mode, simulating the microwave
generator (magnetron), operating at 300 W power, 2.45 GHz frequency.
Green metrics evaluation
The EATOS software, which takes into account the mass economy as well as the environmental
and human health impact of the materials involved, has been applied to assess the “greenness” of the
competing processes. EATOS elaborates all data relative to all materials used in the process (reagents,
solvents, auxiliary materials, products and secondary products) and supplies an evaluation histogram.
It is also possible to compare two or more chemical processes placing side by side their histograms and
standardizing the quantities. In such histograms, the first column is the inverse selectivity S-1 (or mass
index). S-1 is the weight ratio between the sum of all input materials and the final products (Equation
1). The environmental factor E in the second column is the weight ratio between the waste and the
final products (Equation 2). In the third column, EI_in represents S-1 weighted in function of the
weighting factors while column fourth is E weighted in function of the weighting factors. The
weighting factors considered for input materials were price (significance of 50%) and risk expressed
by the R-phrases (significance of 50%). On the other hand, the weighting factors considered for output
materials were toxicity on human being, chronic- and eco- toxicity, each with a significance of 33%.

Molecules 2007, 12
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Equation 1. Mathematical expression of the mass index S-1
substrate g + solvent g + auxiliary material g + cat. g + ...
∑
[ ]
[ ]
[ ]
[ ]
-1
mass index S
=
product g
[ ]
Equation 2. Mathematical expression of the environmental factor E
waste g
∑
[ ]
environmental factor E =
product g
[ ]
References and Notes
1. Bougrin, K.; Loupy, A. Microwave-Assisted Solvent-Free Heterocyclic Synthesis. J. Photochem.
Photobiol. C, Photochem. Rev. 2005, 6, 139-167.
2. Aggarwal, V. K.; de Vicente, J.; Bonnert R. V. A Novel One-Pot Method for the Preparation of
Pyrazoles by 1,3-Dipolar Cycloadditions of Diazo Compounds Generated in Situ. J. Org. Chem.
2003, 68, 5381-5383.
3. Kost, A. N.; Grandberg, I. I. Progress in Pyrazole Chemistry. Adv. Heterocycl. Chem. 1966, 6,
347-429.
4. Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; John Wiley & Sons: New York, 1984; Vol.I.
5. Fulton, J. R.; Aggarwal, V. K.; de Vicente, J. The Use of Tosylhydrazone Salts as a Safe
Alternative for Handling Diazo Compounds and Their Applications in Organic Synthesis. Eur. J.
Org. Chem. 2005, 1479-1492.
6. Bamford, W. R.; Stevens, T. S. The Decomposition of p-Tolylsulfonylhydrazones by Alkali. J.
Chem. Soc. 1952, 4735-4740.
7. Brewbaker, J. L.; Hart, H. The Cyclization of 3-Diazoalkenes to Pyrazoles. J. Am. Chem. Soc.
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Sample Availability: Available from the authors.
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