Solvent-free mechanochemical route for green synthesis of pharmaceutically attractive phenolhydrazones

Article abstract of DOI:10.1039/c4ra10489g

A series of hydrazones, as potential therapeutic agents, were successfully synthesized in a vibratory ball-mill from various substituted organic hydrazines and phenol aldehydes. The degree of conversion was increased by high electronic density on the amino group of the hydrazine reactant, as well as low steric hindrance around both reactive sites. In this particular case, the flexibility of the chain bearing the amino reactive site of hydrazine was highlighted as a factor influencing the reaction rate. The results showed that hydrazones could be obtained with more than a 99% transformation, without concurring by-products. This is highly adapted to the synthesis of active pharmaceutical ingredients, requiring a high level of purity. Owing to the fact that neither an environmentally unadvisable reagent nor additives or catalysts were added to achieve the transformation, this synthesis provides a good example and a prefiguration of an efficient green pharmaceutical process.

Full text of DOI:10.1039/c4ra10489g

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PAPER
Solvent-free mechanochemical route for green
synthesis of pharmaceutically attractive phenol-
hydrazones
Cite this: DOI: 10.1039/x0xx00000x
P. F. M. Oliveira,a M. Baron,*a A. Chamayou,a C. AndréꢀBarrès, b B. Guidettib and M.
Baltas*b
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
A series of hydrazones, as potential therapeutic agents, were successfully synthesized in a
vibratory ballꢀmill from various substituted organic hydrazines and phenol aldehydes. The
degrees of conversion were increased by high electronic density on the amino group of the
hydrazine reactant, as well as low steric hindrance around both the reactive sites. In this
particular case, the flexibility of the chain bearing the amino reactive site of hydrazine was
highlighted as a factor influencing the reaction rate. The results showed that the hydrazones
could be obtained in more than 99% of transformation, without concurring byꢀproducts. This is
highly adapted to the synthesis of active pharmaceutical ingredients, requiring a high level of
purity. Added to the fact that neither environmentally unadvisable reagent, none additive nor
catalysts were added to achieve the transformation, this synthesis provides a good example and
a prefiguration of an efficient green pharmaceutical process.
www.rsc.org/
to enhance properties such as tableting and bioavailability.14ꢀ17
But, the applications of mechanochemistry for pharmaceuticals
Introduction
go beyond associations at a supramolecular level, including the
improvement of active ingredients synthesis, as well as the
design of new potential ones. As example, Tan et al. prepared
sulfonylꢀ(thio)ureas, including antiꢀdiabetic drugs, via
mechanosynthesis.18 But, in particular, mechanochemistry was
used to develop nitrogenꢀcontaining heterocycles, a series well
represented in many therapeutic classes. For example,
phthalazoles,19 phenazines,20 pyrazoles, pyridazinones,21 and
pyrroles22 were obtained by mechanosynthesis, but nonꢀ
heterocyclic nitrogenꢀcontaining molecules were also
synthesized under mechanical solidꢀstate and solventꢀfree
conditions, including peptides23ꢀ25 imines, azomethines,26,27
azines,21 enamines28 and hydrazones.28ꢀ30 In addition to being a
green process, many other attractive aspects of working without
solvent were reported, as the yield was usually higher than 90%
and generally ≥ 99%, and the selectivity reducing the formation
of byproducts and eliminating purification steps for
pharmaceutical ingredients and medicines.
Nowadays there is an urgent need for research and industry to
invent new, clear and less expensive ways to produce
chemicals. All areas of chemistry play important roles in this
context. Among them, catalysis and solventꢀfree systems are
the most explored, using different types of energy to perform
reactions, including microwave, ultrasound, photochemical and
mechanical procedures.1ꢀ3
Mechanochemistry has been used for a long time for
inorganic materials to generate different phases in the area of
mechanical alloying.4,5 More recently, the possibility of using
mechanical energy to synthesize organic molecules in milling
devices opened up a new area of chemistry. Current application
and advances of mechanochemistry can be found to almost all
kinds of organic transformations such as cocrystals formation
and classic organic syntheses.6,7
In the pharmaceutical area, where the concept of Green
Pharmacy is more than ever newsworthy,8ꢀ13 the mechanical
action is used to produce transformation in molecular crystals
The potential application of hydrazones as antioxidant
agents, against sepsis and tuberculosis, as vasodilator to treat
hypertension, and as antitumor agents, shows that the
hydrazones class is considered an important one for new drug
development.31ꢀ34 Until now, they have been mainly
synthesized by classical methods, involving the reaction of an
hydrazine with a carbonyl compound under reflux conditions in
diluted media. An industrial drawback is the amount of solvents
used (ethanol or toluene usually) inducing a lot of waste and
thermal energy needed for an overall time consuming process.
In addition, water formation during the reaction may induce
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incomplete conversions. There are other reports of hydrazones spectra. TLC showed the consumption of the reagents and the
and derivatives under solventꢀfree conditions using microwave consequent appearance of the hydrazone, which was confirmed
1
irradiation to perform them in short times with high yield, but by H and 13C NMR analysis demonstrating final conversions
sometimes the use of small amounts of solvent is required and of up to 99% (and thus yields) depending on the aldehydeꢀ
the amount of reagents used is often around 0.5ꢀ5 mmol.35ꢀ38 In hydrazine couple and no byproducts were detected. In addition,
this context Hajipour et al. reported for the first time the the progress of the reactions can be followed by RAMAN
synthesis of hydrazones and semicarbazone derivatives in analysis. This technique could be a rapid way to control
quantitative yields by milling in mortar with sodium hydroxide mechanochemical reactions without using solvents as reported
and silica gel as solid support acting as facilitator.38 Later on, elsewhere.40 As an example the reaction of syringaldehyde with
Kaupp et al. obtained benzoylhydrazone by milling
a
benzyl carbazate is presented Figure 1.
stoichiometric amounts of benzhydrazine and solid aldehyde or
ketone.28 Similarly, by using the kneading method it was
possible to produce phenylhydrazones in a melt system.29 More
recently, Nun et al. carried out the synthesis of hydrazones in
quantitative yields by milling a large variety of protected
hydrazines with equimolar amounts of carbonyl compounds.
The subsequent Nꢀalkylation of some of them was also reported
by the same authors.30
Herein we report the mechanosynthesis of a phenolꢀ
hydrazones series obtained by the solidꢀstate solventꢀfree
reaction of an aldehyde with the respective hydrazine. We have
already synthesized phenolhydrazones using classical methods
and shown to possess strong antioxidant properties and
cytoprotective effects against the oxidized Low Density
Lipoproteins (LDL) that play a key role in the atherogenesis
process and cardiovascular diseases.39 The mechanosyntheses
of hydrazones were carried out on 2g of reactants between
strictly one equivalent of each partner, in a vibratory ballꢀmill
with a single ball at an average time of 4 hours at room
temperature.
Fig. 1 Raman spectra of hydrazone formation (5a) after 1, 2
and 4 hours of grinding.
Results and discussion
The hydrazones listed in Table 1 were obtained with a high
transformation ratio in grinding times of 4h. H NMR spectra
1
The classical solvated methods to synthesize hydrazones are
generally carried out at low concentration, and require times of
3 to 24 or even 48 hours in reflux of toluene or ethanol in order
to obtain good yields. In this framework we applied the
mechanical energy using a vibratory mill to produce 24
hydrazones (Table 1). In an aim to compare the respective
reactivities of reactants under mechanochemical conditions, a
series of hydrazones were synthesized, some of them already
described using classical methods by our group.31,39 Scheme 1
shows the general solidꢀstate mechanosynthesis of hydrazones
by reacting a hydrazine and an aldehyde.
revealed conversions with respect to the aldehydes and
hydrazines over 90% in almost all the explored syntheses and
no byproducts were found. In Table 1 we have also introduced
conversions (if quantitative) and yields (where purification was
needed) for a series of hydrazones obtained by us under
classical conditions (1mmol of each reagent/30ml of solvent
under reflux for 6ꢀ24h).31,39 For hydralazine hydrochloride
reagent the classical reaction was performed in the absence of
base (triethylamine) and the hydrazone hydrochloride was
isolated.
The mechanochemical route, maybe due to its original
mechanism, seems to be more efficient when comparing the
results with the classical ones under reflux and heat. With
regard to the couplings with isoniazid, hydrazones are obtained
through analogous conversions and yields between the classical
and mechanochemical method. The same is true for benzyl
carbazate where the conversions and yields are almost
quantitative in both cases. For the 2ꢀhydrazinobenzothiazole,
reactions appear better under classical conditions, while for
hydralazine hydrochloride and 3ꢀaminorhodanine the
mechanochemical route appears much more optimal. It is worth
pointing out that with regard to the hydrazones formation with
3ꢀaminorhodanin, conversion and yields can be greatly
improved in favor of the mechanochemical process but also by
performing the later reaction for 8h (tested as an example with
this hydrazine); almost quantitative conversions and yields (no
further purification needed) were obtained. This example is a
clear illustration of the potential of mechanochemistry as a
green route to synthesize active pharmaceutical ingredients.
The reactivity of the hydrazines observed by mechanochemical
Scheme 1 General synthesis of hydrazones in solidꢀsate by coꢀ
grinding of a hydrazine and an aldehyde.
Once the objective of the work was to investigate the
production of hydrazones in solidꢀstate, the mandatory
conditions of choice of reagents was the melting point above
the temperature of synthesis. As the reactions were carried out
at room temperature all the reagents presented in Table 1 fulfill
the requirement. The syntheses with hydralazine hydrochloride
were performed in the presence of 1 equivalent of triethylamine
(TEA) in order to liberate the base from its respective salt.
Table 1 also summarizes for each synthesis, the time of
1
grinding and the conversion obtained by analysis of H NMR
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route could be explained as a result of electronic effects and the
solid form influences.
Table 1 Solids aldehydes (column) and hydrazines (line) used for the synthesis of hydrazones and degree of conversiona for corresponding
hydrazones for 4 hours of grinding as well as the yieldsb from classical method in parentheses.
1
aDetermined by H NMR. In reactions where 1H NMR indicated a conversion lower than quantitative, the degree of conversion was
calculated from the corresponding NMR intensities of the product and the unreacted aldehyde or hydrazine. bYields obtained by the classical
method with 1mmol/30 mL under reflux in times from 8 to 24 h (See Ref. 38 and 46). cThese syntheses with hydralazine hydrochloride were
performed in presence of 1 equivalent of triethylamine (TEA) and the hydrazone was obtained after washing with water to eliminate the TEA
salt. dConversion after 8 hours of grinding.
prolonged time. For the other hydrazines used, the charge
density differences are small, in accordance with analogous
yields obtained under solution conditions.
Electronic effects
Substitution patterns on hydrazines (R1, R2) may influence the
electronic effects and distribution at the terminal NH2 Table 2 Charge density of the –NH2 group from hydrazines
functionality thus modifying its reactivity. In order to get an
insight into the reactivity of the different hydrazines we
determined these effects. Table 2 shows the results of natural
bond orbital (NBO)41 analysis to access the partial atomic
charges of the hydrazines, which was performed in the
B3LYP/6ꢀ311+G(d,p)42 level of theory for the structures of
hydrazines obtained by density functional theory (DFT)
calculated with Gaussian 09 software.43 In a preliminary
approach, these simulations were used to attribute values to the
pure chemical reactivity, making the following comparison
possible: the more negative the charge, the more nucleophilic
or basic the atom. The most striking difference is observed for
3ꢀaminorhodanine where the charge density on the terminal
NH2 group of the hydrazine appears much less than for all other
compounds.
Charge density in –NH2
Hydrazine
(NBO)a
ꢀ0.634
ꢀ0.637
ꢀ0.628
ꢀ0.601
ꢀ0.626
ꢀ0.637
Isoniazid
Hydralazineb
2ꢀhydrazinobenzothiazole
3ꢀaminorhodanine
Benzyl carbazate
Benzhydrazide
aNatural bond orbital (NBO)41 analysis performed in the
B3LYP/6ꢀ311+G(d,p)42 level of theory for the structures of
hydrazines obtained by density functional theory (DFT)
calculated with Gaussian 09 software.43 bNBO was performed
for hydralazine base.
The charge density on the reactive part of the aldehydes
used was also determined. The values obtained under the same
level of theory do not indicate any strong preference in favor of
one of them (all values are between 0.0413 and 0.0414). We
It is reasonable to assume in this case that this effect might
explain the lack of reactivity and the low yields especially
obtained under classical conditions (70% and 37%). The effect
is more pronounced in solution than under mechanochemical
conditions, where total conversion is achieved after a more
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can thus assume that the conversion/yields of the hydrazones literature also support this discussion. Recent studies have
obtained under classical conditions reflect the NH2 reactivity.
shown that the crystal packing of aminorhodanine is governed
Despite the fact that the calculations of partial atomic by H bonding.53 The molecules are linked by N—H…O, N—
charges represent a great panoramic for the prevision of the H…N and N—H…S hydrogen bonds, forming a threeꢀ
nucleophile sites for the explored cases herein, the hydrazines dimensional network that probably reduces the nitrogen
do not follow the expected results in some cases, when reactivity. Similarly, a recent investigation of the crystal
mechanochemical conditions are used. This is especially the structure of isoniazid showed that predominantly CꢀH
⋯
N, Cꢀ
case for isoniazide, benzhydrazide and benzyl carbazate. Based
on this outlook, it is believed that these solidꢀstate
mechanosynthesis are not only guided by electronic aspects but
for the solid characteristics such as the crystal packing, the
solid form, the density, and finally, in summary, the
accessibility of reactive sites in organic solids.
H⋯O and NꢀH⋯N types of intermolecular hydrogenꢀbonding
interactions are responsible for the molecular packing of the
crystal.54 These interactions form an infinite spiral type
structure in the crystal.55 Molecules also form
π—π interactions
in the crystal at a distance of 3.760 A˚. These intermolecular
hydrogenꢀbonds could help explain the lower reactivity of
isoniazid than expected and reducing still more that of
aminorhodanine. The crystal arrangements of the other
hydrazines are probably guided by hydrogen bonds as well, but
no study is described in the literature.
The solid-state role
The mechanisms of solidꢀstate transformations during grinding
were generally attributed to a formation of eutectic melts,44
molecular transport through surfaces due to sublimation45,46 or
in the bulk of material47,48 and to a reaction mediated by
amorphous or metastable crystalline phases.49,50 In this work
we focused in the nature of raw materials that could facilitate
the reaction or make it harder. In solid crystals, molecules are
not free as in gas or in solution, but trapped in the lattice trying
to form the most stable arrangement. All the other surrounding
molecules interact mainly by van der Waals’ forces and/or Hꢀ
bonding, which govern the crystal packing. In this section some
properties of the solid hydrazines were used to discuss the role
of the solidꢀstate in the conversion and reactivity. Crystal
properties of some hydrazines, such as crystallographic data,
the intermolecular interactions resumed here by hydrogen
bonds and the absolute density, were employed to postulate a
balance between the electronic properties, previously discussed
and the steric effects originated from the solid form.
Intermolecular hydrogenꢀbonding is responsible for the
stabilization of the crystal structure. Therefore, in order to
perform a reaction in solid state it is necessary to dissociate the
Hꢀbonding, and, consequently, the stronger the Hꢀbonds, the
higher the energy required to dissociate them. DSC
measurements were performed, but the melting point and the
molar ꢁHfus obtained for the reactants do not explain their
reactivity in this study (See Table 3S, ESI). On the other hand,
as an approximation FTIR spectrometry was used to investigate
the hydrogen bond strength of the starting hydrazines both by
dilution method and temperature variation in the solid state.
The stretching vibrations associated with the NH2 group of
hydrazines were studied depending on the concentration (A = f
In addition to the hydrogen bonding and stacking, the
proximity of the molecules must also influence the accessibility
of the reactive nitrogen. The density of the hydrazines was used
as a first approach to represent the proximity of the molecules.
The values of density were obtained with a helium pycnometer
through the real volume, which does not take the empty spaces
into consideration, and are given in Table 3 in g cmꢀ3.
Table 3 Absolute density (g cmꢀ3) of the solid hydrazines
Hydrazines
Isoniazid
Hydralazine hydrochloride
2ꢀhydrazinobenzothiazole
3ꢀaminorhodanine
Absolute Density (g cm-3)
1.4318
1.4799
1.4525
1.6603
1.2559
1.3006
Benzyl carbazate
Benzhydrazide
The density of benzyl carbazate is the smallest at 1.2559 g
cmꢀ3,
followed by benzhydrazide, isoniazid, 2ꢀ
hydrazinobenzothiazole, hydralazine and 3ꢀaminorhodanine
with 1.6603 g cmꢀ3. Intuitively, a small density could express
farther molecules and more freedom to move. Seen in this way,
3ꢀaminorhodanine has the tighter form and the benzyl carbazate
the looser one, with its reactivity in solid state affected by this
factor. For the 3ꢀaminorhodanine, the higher density further
hampers the access to the reaction site. Isoniazid also has a
higher density than the benzyl carbazate and benzhydrazide and
is less available in the lattice to react. In the same way that in
density charge calculations, hydrazinobenzothiazole occupies a
midterm in the series of density and the same is found for the
conversions always at about 95%.
(concentration) in solution) or
= f (temperature in solid
One can discuss the influence of the mobility of the reactive
site of the hydrazine. The chain bearing the reactive –NH2 can
move more readily as the chain is longer, which most likely
facilitates its accessibility toward the carbonyl group of the
aldehyde. For example, benzyl carbazate presents the longer
one and complementary experiments, not presented in the Table
1, for the synthesis of 5a showed conversions around 88%, 95%
for 1 and 2h grinding, respectively, confirming the ability of
benzyl carbazate to react quickly under these conditions. The
Raman spectra of these runs and the starting materials in solid
state are presented in Figure 1. The presence of hydrazone bond
C=N at 1600 cmꢀ1 and a notable decrease of C=O at 1670 cmꢀ1
of the aldehyde when compared with the syringaldehyde shows
that after only one hour the major part is the product. On the
contrary, the partial intracyclic inclusion of the hydrazino group
of 3ꢀaminorhodanine acts by reducing the freedom of the
state), but the results were generally inconclusive, except for
the aminorhodanine (the lowest reactive hydrazine by
mechanical route). For this hydrazine, in accordance with
literature data,51 the νs(NH2) and νas(NH2) modes were observed
at 3295 and 3325 cm−1 in the IR spectrum, respectively. Two
additional bands were present at ν
3149 and 3233cm−1, which
have been assigned to combination band of the CO stretching
and NH2 bending modes and an overtone of the 1536 cm−1
band, respectively.52 In addition, a linear variation of the
wavenumber at
ν3149 was observed as the temperature
increased (from 25 to 85°C), demonstrating for this hydrazine
the existence of intermolecular interactions in the solid (See
Figure 1S in ESI). On the other hand, the calculated FTIR
spectra (in the gas phase at 298° K) do not reveal any
intramolecular Hꢀbonds (See Table 1S in ESI). Some data from
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reactive site of the hydrazine and the grinding time is extended approach seems to be more efficient in the preparation of
to 8h to attain transformations of around 99%. hydrazones in solidꢀstate and quantities which are more
Finally, Figure 2 summarizes the importance of different important and easier to scale up in comparison with reactions
characteristics of hydrazines acting potentially in these solidꢀ carried out in solution, under microwave36ꢀ38 or using other
state mechanosyntheses of hydrazones.
milling devices.28ꢀ30, 31
In conclusion, these considerations helped us to understand
the reactivity of the hydrazines, which seem to be the result of a
balance of electronic and solid effects. It is still appropriate to
say that within the synthesized hydrazones in this study, no
difference in the final products was found when compared with
the thermal synthesis in reflux of solvent, due, for example, to
another mechanism of reaction or excited state.67 The formation
of intermediate metastable phases during grinding were not
excluded, but not detected. On the other hand, the properties of
the raw materials such as packing guided by hydrogen bonds,
the density and freedom of the molecule fit satisfactorily the
results.
This solventꢀfree synthesis of this series of hydrazones can
be anticipated as a rational and powerful way forward for the
synthesis of active pharmaceutical ingredients.
Acknowledgements
We thank Corinne Routaboul for FTIR studies, Laurène Haurie
(Plateforme GALA®) for Raman spectra and Sylvie Del
Confetto for DSC measurements.
Fig. 2 The electronic and solidꢀstate balance in reactivity of
hydrazines. Orbitals are represented only for –NH2, hydrogen
bonds are represented by dotted lines, density by vertical
arrows and degree of freedom by curved arrows.
Notes and references
Other papers have discussed the electronic effects and the
crystal packing for solidꢀstate reactivity. It was observed that
the products and kinetics are guided by the crystal packing
(subject of topochemistry).56 Through detailed studies and
computer calculations, Gavezzotti had already concluded that a
prerequisite for crystal reactivity is the availability of free space
around the reaction site.57 Years later, Sarma et al. discussed
the role of free volume of some aldehydes for solidꢀstate
bromination and found differences in selectivity from
solution.58 More recently, it has been demonstrated that the
amount and form of energy and how the mechanical energy is
applied concerning the mechanochemical systems, strongly
influence the products and kinetics.59ꢀ61 The difference in
selectivity of the products from solution and solid syntheses has
shown that mechanical energy is capable of surpassing some
classical rules in chemistry leading to the comprehension of the
same molecule in its different states of aggregation and under
different perturbations.62ꢀ67 With regard to the synthesis of
hydrazones the results point to a balance between the electronic
contributions (orbitals), the strength of hydrogen bonds (dotted
lines), the proximity of the molecules, expressed by absolute
density (vertical arrow) and the degree of freedom or
movement (curved arrows) as suggested in Figure 2. What is
not mentioned is that the mechanical energy is essential to favor
the reaction by breaking and destabilizing the solid, which
increases Gibbs free enthalpy,50 and by activating on a macro
and molecular level.
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Several hydrazones were successfully synthesized via the
mechanochemistry route by grinding the aldehydes and
hydrazines in solidꢀstate at room temperature. Conversion ratios
of 85ꢀ99% were obtained depending on the hydrazine/aldehyde
used, but it was demonstrated that the reactions could reach
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illustrated in the case of 3ꢀaminorhodanine series. This
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Mechanical action
Electronic and steric properties of solid reactants were overpassed to produce, quantitatively, pharmaceutically
attractive hydrazones by using green mechanochemical route.