Understanding the Role of Protic Ionic Liquids (PILs) in Reactive Systems: Rational Selection of PILs for the Design of Green Synthesis Strategies for Allylic Amines and β-Amino Esters

Article abstract of DOI:10.1002/cplu.201900318

The reactive behaviour of protic ionic liquids (PILs) has been shown to be governed not only by their chemical structures but also by their global compositions, which include the presence of free acids and bases at equilibrium with ionic pairs. Six PILs composed of primary, secondary, or tertiary alkyl ammonium cations with two couterions, nitrate or acetate, were tested in model reactions with unsaturated substrates. The free species that were naturally present in these liquids were identified by cyclic voltammetry. Only tributylammonium nitrate was found to be mostly composed just of the ionic pair; the other five PILs also contain variable amounts of free acid and amine. In reactive systems, these free species determine the products of the reaction. In particular, allylic amines and β-amino esters were obtained in good yields (91 and 75 %, respectively) by reaction of conjugated dienes and acrylates in the presence of PILs. By taking into account the actual composition of each PIL, it was possible to direct the reaction path towards a specific product with good yields, to ensure acid catalysis, to avoid polymerization of the substrate, and to promote phase transfer of products. These results establish some useful guidelines for the rational design of new PIL-based one-step synthetic strategies.

Full text of DOI:10.1002/cplu.201900318

Accepted Article
Title: Understanding the Role of Protic Ionic Liquids in Reactive
Systems: Rational Selection of PILs for the Design of Green
Synthesis Strategies for Allylic Amines and β-amino Esters
Authors: Maria V Bravo, José L Fernández, Claudia Adam, and
Claudia D Della Rosa
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemPlusChem 10.1002/cplu.201900318
Link to VoR: http://dx.doi.org/10.1002/cplu.201900318
A Journal of
www.chempluschem.org

ChemPlusChem
10.1002/cplu.201900318
FULL PAPER
Understanding the Role of Protic Ionic Liquids in Reactive
Systems: Rational Selection for the Design of Green Synthesis
Strategies for Allylic Amines and -amino Esters
[
a]
[a],[b]
[a]
[a]
María V. Bravo, José L. Fernández,
Claudia G. Adam* and Claudia D. Della Rosa
Abstract: This work demonstrates that the reactive behaviour of
Protic Ionic Liquids (PILs) is governed not only by their chemical
structures but also by their global compositions, which include the
presence of free acids and bases at equilibrium with the ionic pairs.
Six PILs composed by primary, secondary, or tertiary alkyl
ammonium cations with two couterions, nitrate or acetate, were
tested in model reactions with insaturated substrates. The free
species that were naturally present in these liquids were identified by
cyclic voltammetry. We show that only tributylammonium nitrate is
mostly composed just by the ionic pair, and that the other five PILs
also contain variable amounts of free acid and amine. In reactive
systems, these free species determine the products of the reaction.
In particular, allylic amines and -amino esters were obtained with
good yields (91 and 75 %, respectively) by reaction of conjugated
dienes and acrylates in the presence of PILs. By taking into account
the actual composition of each PIL, it was possible to direct the
reaction path towards a specific product with good yields, to ensure
acid catalysis, to avoid polymerization of the substrate, and to
promote phase transference of products. These results establish
some useful guidelines for the rational design of new PIL-based one-
step synthetic strategies.
active participation of ILs in classical synthesis processes leads
to specific effects caused by their unique ionic character, as well
as their particular structures and self-organization. Besides, the
"ionic liquid effect" is not reduced to the mere participation of the
IL as a solvent, so its behaviour in a synthesis process must be
analyzed with caution. In spite of this, there are no clear and
well-founded selection rules for choosing ILs to be used as
solvents in organic synthesis procedures.
Protic Ionic Liquids (PILs) are considered a subset of ILs
that have an available proton on the cation.[4,5] Since the
introduction of ethylammonium nitrate (EAN) to the scientific
community in 1914,[6] PILs have attracted the attention of
researchers in all areas of science, particularly in the last
years.[7-11] The hydrogen bonded (H-bonded) network that they
are able to form, the degree of ionicity, the degree of proton
transfer, among other unique properties, have been studied
exhaustively by different authors.[
12-15]
ILs have as a key property
the possibility of transferring a proton to species that may accept
it. Although this proton is compromised forming a highly
connected, dense and complex H-bonded network, the proton
transfer is still possible. In alkylammoniun-derivate PILs, the
proton transfer has been verified with basic dyes, and even in
some reactive systems an unexpected product corresponding to
the ethylamine (EA) as nucleophile has been reported.[
Because of this, PILs show a great potential for applications in
16]
Introduction
different chemical processes. On that sense, in a previous
work[17] the nucleophilic and acid catalyst behaviour of PILs was
Ionic liquids (ILs) have arisen as new alternative solvents to
volatile organic solvents, being considered in principle
environmentally friendly mainly because they are non-flammable
and non-volatile.[1-3] In recent decades, the synthesis,
characterization, and applications of ILs became an exciting field
of research. Consequently, nowadays it is not strange to find ILs
in several industrial chemical processes. It is well known that
solvent selection is a critical stage for the design of a chemical
process in solution, so this selection must take into account not
only the solubility of reagents and products but also the possible
participation of the solvent in the process under study. The
studied in nucleophilic addition reactions of amines to
substituted aromatic aldehydes. It was noted that, in reactive
systems where acid catalysis was required, the use of EAN was
convenient. The EAN can take part in an acid-base equilibrium
with aromatic aldehydes substituted by electron-donating groups.
Imine products were obtained in one-step from the selected
aldehyde, thus confirming the dual behaviour of EAN as
Brønsted acid and potential nucleophiles in this type of process.
Notwithstanding, the complex reactive behaviour of PILs is
strongly affected not only by the PIL structure but also by its
parent species (free acid and base) that may be accompanying
the PIL in liquid phase, either remaining from the synthesis or
being released from the ionic pair via autoprotolysis equilibria
[
a]
Dr. M.V. Bravo, Dr. J.L. Fernández, Dr. C.G. Adam, Dr. C.D. Della
Rosa
+
-
[18]
(
HB A  HA + B)
after being melted or dissolved. Several
Instituto de Química Aplicada del Litoral (IQAL, UNL-CONICET) and
Facultad de Ingeniería Química, Universidad Nacional del Litoral,
Santiago del Estero 2829, 3000 Santa Fe, Argentina.
E-mail: cadam@fiq.unl.edu.ar
reports have demonstrated the presence of species other than
the PILs that strongly affect their properties and performance as
solvents.[19-21] In many cases, the type of H-bonded network that
[
b]
Dr. J.L. Fernández
is present in the PIL causes a mixture of ions and neutral
species, together with acid-base pairs, leading to very particular
properties.[4,7,8] Besides, the molar relations between neutral and
ionized species that conform the PIL may vary depending of the
used synthesis procedure, as it was shown for example by D.
Programa de Electroquímica Aplicada e Ingeniería Electroquímica
(PRELINE), Facultad de Ingeniería Química, Universidad Nacional
del Litoral, Santiago del Estero 2829, 3000 Santa Fe, Argentina.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

ChemPlusChem
10.1002/cplu.201900318
FULL PAPER
Rogers and co-workers for triethylamine and acetic acid
than the cathodic wave) is detected, which is associated to the
mass-transport controlled electro-oxidation of a free species. It is
unlikely that oxidation of water causes this peak because no
(
AcOH)[9] and by D. Walsh and co-workers for ammonium-based
triflates and trifluoracetates.[21]
[
28,29]
An important number of chemical and biochemical
processes are initiated by the addition of a nitrogen nucleophile
to a carbonyl group. When PILs are used as solvents in these
chemical reactions, new H-bond acceptor sites are generated
upon dissolution of the reactants, and a new reorganization of
ionic and neutral species in equilibrium is established. Thus, the
resulting behaviour of the PIL will strongly depend on the extent
of the autoprotolysis equilibrium displacement and of the
previous existence of free parent species that remained from the
synthesis. On this sense, it can be presumed that not only the
structures but also the actual compositions of the PILs should be
linked to their reactive properties. By understanding this
connection it should be possible to extend the above mentioned
dual behaviour of these PILs (as a Brønsted acid catalyst and
potential nucleophile) to other substrates, bringing new insights
to synthesis strategies. In particular, understanding the
behaviour of a series of alkylammonium-derived PILs would
allow to contribute to the development of a logical criterion that
would be useful for chemists in order to select the best PILs for
a particular application, thus extending their applications beyond
those already identified. In this context, this work reports a
systematic study of the reactive behaviour of different
alkylammonium-type PILs that is associated to a simultaneous
qualitative characterization of the full chemical compositions of
these PILs in liquid phase, assuming that they could be
composed by a mixture of the ionic pair and of the parent
species. More precisely, these PILs were used for the synthesis
of allylic amines from non-polar unsaturated substrates and of -
amino esters from polar , unsaturated esters. Besides, the
compositions of the PILs were characterized by cyclic
voltammetry of microelectrodes in the melted PILs, a technique
that is capable to detect the molecular species (free acid and
amine) in the PIL-based liquid medium.[21,22]
reduction of Pt oxide associated to water traces
was
detected. Even though there are no reported evidences on
electro-oxidation of alkyl amines in ILs, oxidation of dissolved EA
is a feasible reaction[30] that could be taken place at these
potentials causing this peak. As EAN is hermetically stored as a
liquid, during its storage the concentration of dissolved EA can
build up from the ionic pair via autoprotolysis and reach
equilibrium with evaporated EA. The magnitudes of both the
reduction and the oxidation currents should be affected not only
by the concentrations but also by the diffusion coefficients of
nitric acid and EA, respectively, so the molar ratio of these free
species cannot be directly inferred from this data.
Notwithstanding, from these results it is possible to affirm that
EAN contains significant amounts of dissolved HNO
3
and
detectable amounts of dissolved EA, which should be in
equilibrium with the EAN ionic pair.
Results and Discussion
Voltammetric characterization of PILs
On the one hand, the nitrate-based PILs were analyzed. The
cyclic voltammograms (CVs) of EAN, diethylammonium nitrate
(
1
DEAN), and tributhylammonium nitrate (TBAN) are shown in Fig.
. For EAN, the CVs (shown in Fig. 1a) were measured at
different scan rates and over varied potential intervals. The
cathodic discharge of hydrogen from free nitric acid[19,22-24] is
verified in the cathodic scan at E < -0.5 V. The attainment of a
voltammetric peak whose current magnitude depends on the
scan rate indicates that this process is controlled by the low
mass transport rate of nitric acid in this medium.[25] Upon
extending the potential range to more cathodic values (inset
-
1
Figure 1. CVs of a Pt microelectrode at 60°C in: (a) EAN at 0.1 V s (i) and
0
graph), a second reduction current increment is detected at E < -
-1
-1
.025 V s (ii). The inset graph shows CVs measured at 0.05 V s (iii)
including a CV measured over an extended cathodic potential range. (b)
DEAN at 0.1 V s before (i) and after (ii) addition of DEA. The inset graph
shows the same CV with an amplified cathodic potential region. (c) TBAN at
26]
1
.2 V (also shown in previous reports for EAN[ and for other
PILs[16,27]), which is probably caused by the reduction of
ethylammonium. Furthermore, at anodic potentials (E > 0.7 V) a
scan-rate dependant oxidation peak (with much lesser current
-1
-
1
0
.1 V s before (i) and after (ii) addition of TBA.
This article is protected by copyright. All rights reserved.

ChemPlusChem
10.1002/cplu.201900318
FULL PAPER
Similarly, the CVs measured in DEAN immediately after
AcOH.[31] However, these currents are not stable during the
timeframe of the experiment and decrease upon successive
cycling. This current drop can be explained in terms of a
continuous loose of AcOH by evaporation. Moreover, by adding
0.1 mL of glacial AcOH the reduction and oxidation currents are
re-established (Fig.2a-(II)), but they drop again after successive
cycling. In contrast, the CVs measured in DEAA at 60°C
immediately after complete melting (Fig. 2b-(i)) shows a cathodic
shoulder for the hydrogen discharge from AcOH at E < -0.5 V
and an oxidation current at anodic potential (E > 1 V). Through
the addition of pure DEA (inset graph) it was verified that this
anodic current comes from the oxidation of DEA (similarly to
DEAN). The addition of DEA also caused a decrease of the
melting (Fig. 1b) show the cathodic discharge of hydrogen from
nitric acid at E < -0.5 V as a voltammetric shoulder before the
electro-reduction of diethylammonium at E < 1 V takes place.
Besides, just a slight anodic current is observed at E > 0.9 V.
Upon addition of 0.1 mL of pure diethylamine (DEA), this
oxidation current is clearly increased, which demonstrates that it
is caused by the electro-oxidation of dissolved DEA. Moreover,
the DEA addition also caused a decrease of the shoulder current
(
inset graph), which indicates a decrease of the free nitric acid
concentration due to its combination with added DEA to form the
ionic pair. These results indicate that after being melted or
dissolved, DEAN contains detectable amounts of free nitric acid
and DEA. In contrast, Fig. 1c shows the CVs measured in TBAN, hydrogen discharge current (Fig. 2b-(ii)), indicating the
where neither the reduction of nitric acid nor the oxidation of
tributhylamine (TBA) can be detected. The CV is almost
insensitive to the addition of pure TBA, which in fact seems to be
insoluble in the TBAN (a second phase is formed). These results
indicate that TBAN is mostly composed by the ionic pair, and
contains negligible amount (if any) of dissolved nitric acid and
TBA. On the other hand, the acetate-based PILs were analyzed.
The CVs of ethylammonium acetate (EAA), diethylammonium
acetate (DEAA), and tributhylammonium acetate (TBAA) are
shown in Fig. 2. Firstly, the CVs measured in EAA at 89°C
immediately after its complete melting are shown in Fig. 2a-(I). A
cathodic current corresponding to the discharge of hydrogen
from AcOH is observed at E < -0.5 V, and an anodic current is
established at E > 1.6 V. Such process is too anodic (as
compared to previous CVs) to be assigned to the oxidation of
free EA, and is most likely coming from the oxidation of free
consumption of AcOH by reaction with added DEA to form the
DEAA ionic pair. Moreover, after addition of glacial AcOH (Fig.
2b-(iii)) the reduction current is re-established and the DEA
oxidation current decreases due to its reaction with part of the
added AcOH. From these results, it can be concluded that the
DEAN in liquid phase contains important amounts of dissolved
AcOH and detectable amounts of DEA, presumably generated
by the autoprotolysis equilibrium. Similarly, the CVs of TBAA
(Fig. 2c-(i)) also show the cathodic shoulder caused by the
reduction of AcOH (E < -0.5 V) and a significant anodic peak
from the oxidation of free TBA (E > 0.7 V). Thus, it is clear that
the PIL TBAA contains important amounts of AcOH and TBA in
equilibrium with the ionic pair. Moreover, the addition of glacial
AcOH produces an increase of the cathodic current and a
decrease of the anodic peak (Fig. 2c-(ii)) due to the
displacement of the autoprotolysis equilibrium.
-
1
Figure 2. CVs of a Pt microelectrode in: (a) EAA at 89°C measured at 0.1 V s . (I) CVs acquired immediately after complete melting of the LIP (rows indicate the
chronological order of the CVs); (II) CVs measured before (i) and after (ii) addition of AcOH. (b) DEAA at 60°C measured at 0.1 V s-1 acquired immediately after
complete melting of the LIP (i), after adding 0.2 mL of DEA (ii), and after adding 0.1 mL of AcOH to the previous solution (iii). Inset graph: CVs measured at 0.025
V s-1 before (i) and after (ii) addition of DEA. (c) TBAA at 60°C measured at 0.1 V s-1 before (i) and after (ii) adding 0.1 mL of AcOH.
This article is protected by copyright. All rights reserved.

ChemPlusChem
10.1002/cplu.201900318
FULL PAPER
In summary, the reported voltammetric studies allowed to
allow the development of new synthetic strategies for allylic
amines in one stage.
verify that the analyzed PILs, once they are in liquid phase, may
contain varied amounts of the neutral parent species that are
qualitatively summarized in Table 1. In general, in nitrate-based
PILs the amounts of these free species decrease as the amine
becomes more substituted. In acetate-based PILs, these
amounts were always significant, except for the EA in EAA,
which only contained an excess of AcOH. These free
compounds may affect the catalytic activity and selectivity of
these PILs to drive the reactions through specific reaction routes.
Table 2. PILs and unsaturated systems used in the different reactions
Unsaturated
Compound
PILs
1
2
3
EAN / EAA
Table 1. Qualitative content of species in the analyzed melted PILs at 60°C
4
5
6
PIL
Free acid / amount
Free ammine /amount
EAN
HNO
HNO
HNO
3
3
3
/ significant
/ detectable
/ undetectable
EA / detectable
DEAN
TBAN
EAA[b]
DEAA
TBAA
DEA / detectable
TBA / undetectable[a]
EA / undetectable
DEA / detectable
TBA / significant
AcOH/significant
AcOH/significant
AcOH/significant
7
[
a] TBA is insoluble in TBAN. [b] Analyzed at 89°C.
O
Reactive behaviours of PILs with non-polar reactants
Allylic amines have become interesting targets for synthetic
organic chemistry due to the presence of this functionality in
several naturally occurring compounds.[32-35] The usefulness of
these compounds in organic synthesis is well documented.[36-39]
Procedures to synthesize allylic amines generally involve more
than one reaction stage and use very specific catalysts.[40] In this
context, the reactive behaviour of all previously analysed
alkylammonium-based PILs were tested against 2-methyl-1,3-
4
In conditions of acid catalysis and high temperature usually
employed in many organic synthesis procedures, polymerization
of the dienes is generally favoured.[41] Consequently, an excess
butadiene (4) (isoprene). In addition,
a number of other
unsaturated systems, specifically alkenes, alkynes, and
conjugated dienes, were evaluated in EAN and in EAA. Table 2
summarizes the PILs and the unsaturated compound used in
each case, such as 1-octene (1), cyclohexene (2), 1-heptyne (3),
of the diene should be used to achieve a high yield of the
desired product. Under the reaction conditions here selected,
the polymerization reaction was not observed. This fact should
be taken into account because dienes participate in numerous
organic synthesis reactions, where it is common to use an
excess of diene for the above mentioned reason. On the other
hand, it is important to highlight that DEAN presented a reactive
behaviour with isoprene that was similar to that previously
described for EAN, but with lower yields. Besides, TBAN was
observed not to react with the tested unsaturated system. These
results are summarized in Table 4.
So far, it could be inferred that the chemical structure of
the reagent and the ionicity of the PIL cation play crucial roles on
the obtained results (particularly on the yield of the main
product). On this sense, conjugated dienes leaded to higher
yields than alkenes and alkynes. Besides, as the PIL ionicity is
2
1
-methyl-1,3-butadiene (4), 1,3-cyclopentadiene (5), 1-methyl-
,3-cyclopentadiene (6), as well as aromatic heterocyclic dienes
like furan (7). These reactions were carried out under mild
conditions to promote the acid catalysis by PILs and to avoid by-
products, which allowed framing these reactions within the
'
Green Chemistry'.
For all cases, a single main product was found, showing a
great specificity in these PILs. Scheme 1 shows the products
obtained for the selected reactive systems with EAN and with
EAA. It can be observed that the behaviour of these PILs in
unsaturated systems is not passive. The analysis of the product
structures shows that these PILs can react with nonpolar
substrates even under mild conditions. The amounts of products
obtained in EAN were always much larger than those obtained
in EAA, so the yields were calculated only for the first PIL (Table
affected by conjugative, substituent, and symmetry effects on
the cation,[12] a specific reactive behaviour observed for a
3). It can be observed that best yields are obtained when the
particular PIL cannot be generalized to others, even to those
that belong to the same family. Within a reactive system, the
final product and yield will depend on several factors such as the
chemical structure of the reactants, the degree of proton transfer,
and the identity and ratio of all present species.
substrates are conjugated dienes; in these cases the main
products are the corresponding allylic amines. In particular,
when using isoprene, an excellent yield (91 %) was obtained for
the allylic amine 11. In summary, the reactive behaviours of
these unsaturated compounds with PILs informed in this work
This article is protected by copyright. All rights reserved.

ChemPlusChem
10.1002/cplu.201900318
FULL PAPER
Scheme 1. Products obtained when the different unsaturated compounds react in a molar ratio with EAN or EAA.
Table 3. Reaction of EAN with unsaturated compounds 1-7 in 1:1 molar ratios
further purification, thus making organic synthesis processes
cleaner and easier (one-step).
at 50°C during 24 h
From these results, it is evident that the reactivity of the
PILs with non-polar unsaturated substrates is strongly affected
both by the amine substitution degree and by the nature and
Unsaturated compound
Yield (%)
Product
1
2
3
4
5
6
7
10
20
Traces
91
55
8
9
3
availability of the parent acid (HNO /AcOH). The higher yields of
10
11
12
13
14
the reaction when using EAN (91%) and DEAN (82%) could be
related to the presence of free nitric acid, which may facilitate
the H-transfer to the diene acting as an intermediary. However,
in the acetate-based PILs the yields were significantly lower than
in the respective nitrates (37% and 14%, respectively), which
suggests that the acidity strength of the free acid may play an
important role in this process. This is clear evidence that the
acidity of the alkylammonium cation in the ionic network of the
PIL is not enough for taking care of an efficient H-transfer
catalysis on non-polar substrates. Besides, a decrease of the
yields was evident upon increasing the amine substitution, both
for nitrates and acetates. As a limit case, the yields were almost
null in TBAN and in TBAA. Even though such effect could be
caused by a decrease of the nucleophilic strength of the amines
as they become more substituted, the low amount of the free
strong acid (particularly in TBAN) could also be a key factor.
Moreover, no clear trend was observed between the reaction
yield and the amount of free amine, which strengthen the
hypothesis that the alkylammonium cation supplies the amine
that acts as nucleophile in the reaction.
60
50
Taken into account the above description, we analysed the
reactive behaviour of these PILs with acetate counterion (EAA,
DEAA, and TBAA) and isoprene as reactive. The yields for EAA
and DEAA were significantly lowers than those obtained when
using the respective nitrates (see Table 4), and no reaction was
observed with TBAA (similarly to TBAN). Moreover, two well-
defined phases were observed in the reactor when the final
conversion was reached, specifically with EAA and DEAA. By
1
H-NMR analysis, it was confirmed that one of these phases was
the pure product. As a first hypothesis, this phenomenon may be
attributed to the possible solubility differences of the product in
these PILs, respect to their homologous with counterion nitrate.
Thus, the advantage of working with acetates, in addition to
involving simple experimental procedures, would be that the
products can be separated from the crude reaction without
This article is protected by copyright. All rights reserved.

ChemPlusChem
10.1002/cplu.201900318
FULL PAPER
Table 4. Summary of results
Biphasic
System
Polymerization
Reaction
Reactive
Conditions
System
Product Yield (%)
Presence of free acid
Presence of free amine
Product
Detectable by CV
Detectable by CV
Detectable by CV
4
+EAN
+EAA
No
No
No
91
37
11
4
Undetectable by CV
Yes
4
+DEAN
Detectable by CV
Detectable by CV
Undetectable by CV
Detectable by CV
Detectable by CV
Detectable by CV
Undetectable by CV
Detectable by CV
N,N-Diethyl -3-
methyl-2-buten-
No
No
No
-
82
6
0°C,
4
+DEAA
Yes
14
1-amine
12-24 h
4
+TBAN
+TBAA
-
-
-
Undetectable
Undetectable
4
-
-
1
6+EAN
Detectable by CV
Detectable by CV
PBA
18
No
Yes
9
8
1
6+EAA
7+EAN
7+EAA
Detectable by CV
Detectable by CV
Detectable by CV
Undetectable by CV
Detectable by CV
Detectable by CV
Yes
No
No
Yes
No
75
98
73
1
PMMA
19
1
Yes
In order to rule out the possibility that an ammonium salt
and are also useful in fine chemicals and pharmaceuticals.[42,43]
Therefore, the reactions of PILs with , unsaturated esters
methyl methacrylate (15) and butyl acrylate (16) were designed,
which were studied under the same previously used conditions
(50-60°C, 24 h). For non-polar reactants, the presence of free
nitric acid was required to attain good product yields, and the
acidity of free acetic acid was not strong enough to drive the
acid catalysis. However, in this case free nitric acid may lead the
reaction toward undesired products. Particularly its reactivity
with acrylates could induce polymerization process. For that
reason, EAA was selected as a first choice to react with the
unsaturated esters, hoping that the catalytic strength for H-
transfer of this PIL (or of the free AcOH that it contains) will be
high enough to react with these polar substrates. As a result, the
obtained products were the - amino esters methyl 2-methyl-3-
(methylamino) propanoate (17, 75 %) and butyl 3-(ethylamino)
propanoate (18, 73%) with very good yields (Scheme 2).
that does not form a PIL in the presence of free acid could have
a similar reactive behaviour, we applied the same previously
described methodology using unsaturated compounds and
amine salts such as ammonium nitrate and benzyl ammonium
nitrate. No reaction product was observed, not even under
conditions more drastic than those used in this work. This fact
confirms the importance of the unique reaction conditions that
are established in PIL-based media. These PILs form a special
H-bond network that induces a particular self-organization of
ions, resulting in polar and non polar nano-domains with
particular behaviours. In summary, up to this point, the
experiments showed that non-polar conjugated dienes, alkenes,
and alkynes react with these PILs under mild temperature
conditions leading to the corresponding allylic amines as the
only product. The reaction yields were strongly dependant on
the acidity of the free parent acid (nitrate > acetate) and on the
nucleophilic character (or substitution degree) of the amine that
conforms the PIL (EA > DEA > TBA).
Reactive behaviours of PILs with polar reactants
In order to explore the reactivity of these PILs for the
nucleophilic addition on unsaturated polar substrates and also to
discard an "exclusive" behaviour just for conjugated dienes, they
were used in Michael's reactions for obtaining -amino esters.
The specific dual behaviour of PILs could be very useful for
developing and/or modifying synthesis reactions of biologically
interesting products like these esters. On that sense, the
formation of carbon–nitrogen bonds by simple addition of
amines to double bonds is the focus of increasing interest and
widely used in organic synthesis owing to the importance of the
resultant -amino compounds. These -amino carbonyl
compounds are versatile intermediates for the synthesis of a
variety of biologically important natural products and antibiotics,
Scheme 2. Products of aza-Michael´s addition.
Results showed that the selected reactive system was very
efficient for the aza-Michael´s addition reaction, and the product
was transferred to a new phase during the reaction course. As
predicted, when the counterion was acetate, it was possible to
avoid polymerization of acrylates. Moreover, as expected, when
the counterion was nitrate it was verified that the corresponding
polymers of 15 or 16 were the main products, which were likely
formed due to the presence of free nitric acid. The possibility to
direct the reaction towards one way or the other through a
proper selection of the PIL counterion is a quite interesting
This article is protected by copyright. All rights reserved.

ChemPlusChem
10.1002/cplu.201900318
FULL PAPER
finding. The reaction direction can be controlled without major
efforts towards obtaining the - amino esters exclusively. In
addition, for these reactive systems, a similar dependence on
the PIL cation structure was observed, i.e. the yield of the
reaction is greater the less substituted is the PIL cation (or the
less hindered is the amine generated as a consequence of the
PIL action as Brønsted acid). This is clear evidence that the
catalytic activity of these PILs is not a unique or specific
behaviour of a particular reactive system. The rational selection
of PILs allows driving the reaction towards the expected product.
All the results obtained in this work are summarized in Table 4,
including the semi-quantitative voltammetric characterization.
logical to consider the continuous regeneration of PILs. Thinking
about this, if the pure amines were charged after the first
reaction/separation cycle, it would be possible to neutralize the
nitric acid generated as a residue of the reaction. This fact would
improve the process design in several aspects: waste disposal
to the environment can be avoided, PILs can be reused, and a
methodology to obtain these products in a continuous way can
be developed.
Experimental Section
Materials. Diethylammine, tributhylamine, isoprene, methyl methacrylate,
and buthyl acrylate (> 99%) were obtained from Sigma-Aldrich. The
ethylamine (70% in water), was from Sigma-Aldrich. The acids used for
the synthesis of PILs were nitric acid (69% in water) and anhydrous
acetic acid (> 99%) from Sigma-Aldrich.
Conclusions
It was demonstrated that a deep knowledge of the PIL properties
and compositions is essential both to extract all their potentials
and to redirect reactions within the 'Green Chemistry' area. It is
clear that in most cases PILs are not composed only by ions.
Then, not only the properties of the ionic network that they form
but also the presence of accompanying dissolved species affect
the course of the reactions. From the voltammetric analysis
performed on six alkyl ammonium nitrates/acetates here studied,
it was demonstrated that only TBAN is mostly composed just by
the ionic pair, and that the other five PILs also contain variable
amounts of free acid and amine (in addition to the ionic species).
Thus, the variable compositions of these systems explain the
difficulties for predicting the behaviour of a single family of PILs
against a certain reactive system. In this work, it is demonstrated
that both the chemical structures of the PIL ions and the global
compositions are the responsible of the observed behaviours in
reaction systems.
Instrumentation. 1H-NMR and 13C-NMR spectra were recorded on a
Bruker 300 MHz instrument with deuterated solvent and
tetramethylsilane (TMS) as internal reference. FTIR spectra were taken
on neat samples by using
a Shimadzu IR Affinity-1 (ATR-FTIR)
spectrometer. Voltammetric experiments were carried out using
CHI1140B potentiostat.
a
Preparation of Protic Ionic Liquids. All PILs were prepared by
neutralization of amine with suitable acids by following previously
reported procedures.[16,44] The dropwise addition of the acid to the amine
2
was carried out under a N atmosphere in a two-neck round bottom flask
kept an ice-water mixture. The mixture was then stirred at room
temperature for several hours. To ensure a complete neutralization
reaction, a slight excess of amine was added, after which it was removed
along with water by heating at 80°C for 48 h under vacuum. The obtained
1
PILs were analysed using H-NMR and FTIR.
For EAN and its homolog PILs, the free acid that is
dissolved in the ionic media seems to have enhanced acid
properties, as these PILs are capable to drive acid catalysis on
non-polar dienes and the polymerization of unsaturated esters.
On the contrary, for the equivalent acetate-based PILs
containing great amounts of free acetic acid, such acid
properties are insufficient to drive acid catalysis on non-polar
dienes but they are strong enough to catalyze it on unsaturated
esters, avoiding their polymerization. Therefore, a new one-step
methodology was developed for the synthesis of allylic amines
from conjugated dienes and -amino esters through the aza-
Michael´s reaction with acrylates as a starting material. This last
reaction was developed under acid catalysis, with phase transfer
of the main product, and without observation of products
resulting from the substrate polymerization. Thus, if the target
molecule is the allylic amine, PILs derived from primary and
secondary amines, with nitrate as counterion, are more suitable.
Otherwise, if the target molecule is a -amino ester, PILs with
acetate as counterion should be the best choice.
Synthesis procedures. All the synthesis were carried out in an ampoule
equipped with a magnetic stir bar containing 1 mmol of the corresponding
substrates, 1 mmol of PILs and 0.2 mL of acetonitrile. The ampoule was
sealed and then heated in a bath under continuous stirring. All the
reactions were carried out under mild conditions (50-60 °C, 24 h).
Products were fully characterized by 1H-NMR and 13C-NMR
spectroscopy (see Supporting Information). In particular, for the allylic
amines synthesized using PILs with nitrate as counterion, after the
reaction time was completed, the reactor was cooled and opened. The
2 2
products were extracted with Cl CH , then the solution was evaporated
and the residue was purified by column chromatography on silica using
hexane–ethyl acetate mixtures as eluent. For the allylic amines or -
amino esters synthesized using EAA or DEAA, after the reaction time
was completed, the reactor was cooled and opened. Two well-defined
phases were observed. The upper organic phase was separated and
pre-concentrated by evaporation for 1-2 h. For allylic amines the organic
phase was analyzed, but for -amino esters this phase was cleaned up
on silica using hexane–methanol mixtures as eluent. The yields were
calculated after isolation and purification of the products.
Voltammetric measurements. All the PILs were characterized by cyclic
voltammetry of Pt microelectrodes for detecting free electroactive species
According to these findings, the selection of PILs should
not be random. The challenge is to design tailor PILs which
would allow to tune the reaction conditions, thus achieving a
specific performance with the minimal environmental impact.
Moreover, within the framework of the 'Green Chemistry' it is
(i.e. PIL´s parent species, water, and other impurities). These
experiments were carried out in a thermostatted low-volume (3 mL) three
electrode cell with watertight seal provided by a threaded Teflon cap. The
working electrodes were disk-shaped 25-m-diameter Pt microelectrodes
that were fabricated by heat-sealing Pt wires into borosilicate glass
This article is protected by copyright. All rights reserved.

ChemPlusChem
10.1002/cplu.201900318
FULL PAPER
capillaries, followed by polishing of the capillary cross section.[45] A Pt
wire located in the same vessel was used as counter-electrode, and
another Pt wire was used as quasi-reference electrode (QRE).[46] The Pt
wire of the QRE was placed inside a Luggin-Habber capillary that
contained the same cell electrolyte. The rest potential of the QRE was
calibrated in each analyzed PIL by adding ferrocene (Fc) and measuring
the standard potential of the Fc/Fc+ couple vs. the QRE by cyclic
voltammetry on the Pt microelectrode. All potentials are reported
referenced to this value measured in each PIL. For operation, the cell
was loaded at room temperature (25 °C) with the liquid (EAN, TBAN, or
TBAA) or the solid (DEAN, EAA, or DEAA) PIL, and closed with the
Teflon cap that supported all the electrodes. Then, in order to melt those
PILs that were solid, the cell temperature was raised to 60 °C, excepting
for the EAA that required 89°C. The resulting PIL volume was  1.5 mL.
[10] K. Dong, S. Zhang, J. Wang, Chem. Com. 2016, 52, 6744.
[11] L. Yi Qi, G. Yan, L.X. Yan, L. Hao Ran, Sci. China. Chem. 2012, 55,
1688
[12] J.-P. Belieres, C. Austen Angell, J. Phys. Chem. B 2007, 111, 4926.
[13] D.R. MacFarlane, K.R. Seddon, Aust. J. Chem. 2007, 60, 3.
[14] P.A. Hunt, C.R. Ashworth, R.P. Matthews, Chem. Soc. Rev. 2015, 44,
1257.
[15] K. Dong, S. Zhang, J. Wang, Chem. Commun. 2016, 52, 6744.
[16] C.G. Adam, M.V. Bravo, P.M.E. Mancini, Tetrahedron Lett. 2014, 55,
148.
[17] C.G. Adam, G. Fortunato, P.M.E. Mancini, J. Phys. Org. Chem. 2009,
22, 460.
[18] R. Kanzaki, H. Doi, X. Song, S. Hara, S. Ishiguro, Y. Umebayashi, J.
Phys. Chem. B 2012, 116, 14146.
The electrolyte was saturated with inert gas (dry N
2
) by continuous
[19] M. Yoshizawa, W. Xu, C.A. Angell, J. Am. Chem. Soc. 2003, 125,
15411.
bubbling. CVs were measured between a cathodic potential that was
negative enough (< -0.7 V) to detect hydrogen evolution from the free
acid,[21-23] and an anodic potential that was high enough (> 1.2 V) to
detect the electro-oxidation of free alkyl amine[30] or AcOH.[31] The
potential incursion over such anodic values also allowed to keep the
electrode free of fouling by amine or acid adsorption.[22,24] In order to
confirm the assignment of voltammetric waves to the reduction or
[20] G.L. Burrell, I.M. Burgar, F. Separovic, N.F. Dunlop, Phys. Chem.
Chem. Phys. 2010, 12, 1571.
[21] S.E. Goodwin, D.E. Smith, J.S. Gibson, R.G. Jones, D.A. Walsh,
Langmuir 2017, 33, 8436.
[22] C.L. Bentley, A.M. Bond, J. Zhang, Annu. Rev. Anal. Chem. 2018, 11,
397.
oxidation of
a
specific free species, when possible, pure liquid
[23] Y. Meng, L. Aldous, S.R. Belding, R.G. Compton, Phys. Chem. Chem.
Phys. 2012,14, 5222.
components AcOH, DEA, or TBA were added during the experiments by
using a needle connected to a micropipette. The absence of voltammetric
peaks that could be associated to the reduction of platinum oxide formed
from water traces allowed to confirm the inexistence of water at
detectable levels.[28,29] Moreover, voltammetric peaks from electroactive
impurities were not detected in the CVs, which confirms the high purity of
the analyzed PILs.
[24] S.E. Goodwin, S. Muhammad, L.P. Tuan, D.A. Walsh, J. Electroanal.
Chem. 2018, 819, 187.
[25] D.A. Walsh in Electrochemistry in Ionic Liquids, Vol. 1 (Ed.: A.A.J.
Torriero), Springer, Cham, 2015, pp. 113-141.
[26] J.A. Bautista-Martinez, L. Tang, J.-P. Belieres, R. Zeller, C.A. Angell, C.
Friesen, J. Phys. Chem. C 2009,113, 12586.
[
27] C.L. Bentley, A.M. Bond, A.F. Hollenkamp, P.J. Mahon, J. Zhang, J.
Phys. Chem. C 2015,119, 21828.
[
[
28] A. García-Mendoza, J.C. Aguilar, Electrochim. Acta 2015,182, 238.
29] C.L. Bentley, A.M. Bond, A.F. Hollenkamp, P.J. Mahon, J. Zhang, J.
Phys. Chem. C 2014, 118, 22439.
Acknowledgements
This work was supported by Universidad Nacional del Litoral
[30] T. Luczak, J. Appl. Electrochem. 2007, 37, 269.
(
CAI+D 2016 234), Agencia Santafesina de Ciencia, Tecnología
[31] S. Beyhan, J.M. Léger, F. Kadırgan, Appl. Surf. Sci. 2014, 321, 426.
[
32] R.B. Cheikh, R. Chaabouni, A. Laurent, P. Mison, A. Nafti, Synthesis
983, 9, 685.
33] M. Hagihara, N.J. Anthony, T.J. Stout, J. Clardy, S.L. Schreiber, J. Am.
e Innovación (IO 2010–035-16) and Agencia Nacional de
Promoción Científica y Tecnológica (PICT 2017 1340). Special
thanks are due to Matías Simonetto for his technical assistance.
1
[
Chem. Soc. 1992, 114, 6568.
[
[
[
34] A. Stütz, Angew. Chem. Int. Ed. 1987, 26, 320.
35] R.D. Allan, G.A.R. Johnstone, B. Twitchin, Neurosci. Lett. 1977, 4, 51.
36] A. Le Darz, U. Castelli, N. Mokhtari, A. Martin-Mingot, J. Marrot, F.
Bouazza, O. Karam, S. Thibaudeau., Tetrahedron 2016, 72, 674.
37] M. Kawatsura, T. Hirakawa, T. Tanaka, D. Ikeda, S. Hayase, T. Itoh,
Tetrahedron Lett. 2008, 49, 2450.
Keywords: Allylic Amines • -Amino Esters • Ionic Liquids •
Organic Synthesis • Voltammetry
[
[38] Y. Ichikawa, T. Ito, T. Nishiyama, M. Isobe, Synlett 2003, 7, 1034.
[39] G. Deleris, J. Dunogues, A. Gadras, Tetrahedron 1988, 44, 4243.
[40] E. Aguilar, J. Joglar, I. Merino, B. Olano, F. Palacios, S. Fustero,
Tetrahedron 2000, 56, 8179.
[
[
1]
2]
C. Chiappe in Ionic Liquid in Synthesis (Eds.: P. Wasserscheid, T.
Welton), Wiley-VCH, Weinheim, 2nd edn, 2008, pp. 265-292.
[41]
S.V. Kostjuk, RSC Adv. 2015, 5, 13125.
[
[
42] L.-W. Xu, J.-W. Li, S.-L. Zhou, C.-G. Xia, New J. Chem. 2004, 28, 183.
M.J. Earle in Ionic Liquid: Industrial Application for Green Chemistry
43] K.P. Dhake, P.J. Tambade, R.S. Singhal, B.M. Bhanage, Tetrahedron
Lett. 2010, 51, 4455.
(ACS Symposium Series) (Eds.: R.D. Rogers, K.R.Seddon), American
Chemical Society, Washington, 2002, pp. 90-105.
[
[
44] D.F. Evans, A. Yamauchi, R. Roman, E.Z. Casassa, J. Coll. Interface
Sci. 1982, 88, 89.
[
[
[
[
[
3]
4]
5]
6]
7]
R.D. Rogers, K.R. Seddon, Science 2003, 302, 792.
T.L. Greaves, C.J. Drummond, Chem. Rev. 2008, 108, 206.
C.A. Angell, N. Byrne, J.-P. Belieres, Acc. Chem. Res. 2007, 40, 1228.
P. Walden, Bull. Acad. Imper. Sci. (St. Petersburg) 1914, 8, 405.
M. Shen, Y. Zhang, K. Chen, S. Che, J. Yao, H. Li, J. Phys. Chem. B
45] F.F. Fan, J.L. Fernández, B. Liu, J. Mauzeroll, C.G. Zoski in Handbook
of Electrochemistry(Ed.: C.G. Zoski), Elsevier, Amsterdam, 2007, pp.
189-197.
[
46] A.A.J. Torriero in Electrochemistry in Ionic Liquids, Vol. 1 (Ed.: A.A.J.
Torriero), Springer, Cham, 2015, pp. 75-111.
2017, 121, 1372.
[
[
8]
9]
K. Chen, Y. Wang, J. Yao, H. Li, J. Phys. Chem. B 2018, 122, 309.
P. Berton, S.P. Kelley, H. Wang, R.D. Rogers, J. Mol. Liquids 2018,
269, 126.
This article is protected by copyright. All rights reserved.

ChemPlusChem
10.1002/cplu.201900318
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here: max.
width: 5.5 cm; max. height: 5.0 cm))
Layout 2:
FULL PAPER
O
O
María V. Bravo, José L. Fernández,
Claudia G. Adam*, Claudia D. Della
Rosa
N
H
N
H
EAN
PILs
EAA
O
Page No. – Page No.
O
Understanding the Role of Protic
Ionic Liquids in Reactive Systems:
Rational Selection for the Design of
Green Synthesis Strategies for Allylic
and -amino Esters
Protic ionic liquids (PILs) have active roles when performing as solvents in
synthesis reactions. The main product of a reaction strongly depends not only on
the PIL´s chemical structure and properties but also on its global composition
(
particularly the presence of free acid). Thus, new one-step synthesis strategies
were proposed for allylic amines and -amino esters from conjugated dienes and
acrylates, respectively, with very good yields (91-75%).
This article is protected by copyright. All rights reserved.