Research on solubility and bio-solubility of amino acids ionic liquids

Article abstract of DOI:10.1016/j.molliq.2016.11.071

Herein, the synthesis of L-(+)-α-(positive butyl)-leucine ethyl ester ionic liquids with anions based on bromide (Br^?), terafluoroborate (BF₄^?) and hexafluorophosphate (PF₆^?) were presented. The structures and purities of these amino acids ionic liquids (AAILs) were characterized by ¹H NMR and the determinations of water content. The interaction energies of AAILs-solvents/amino acids and dipole moment of AAILs were obtained through ab initio at MP2/6-311G?++(2d, p). The relationships between the solubility of AAILs and common solvents, molecular structure and the interaction energies of AAILs-solvents along with the influences of temperature and molecular structure on the bio-solubility of AAILs were discussed systematically. The results revealed that the solubility of the title AAILs increased firstly and then decreased with decreasing dielectric constant of solvent. With the dipole moment of AAILs and hydrogen bond interaction increasing, the solubility in polar solvents had an increasing trend. With the interaction energies of AAILs-solvents becoming bigger, AAILs can be easily dissolved in the solvents. The dissolution of amino acids in AAILs was largened with temperature increasing. Additional, the ease or difficulty of dissolution for amino acids in AAILs can be predicted by theoretical calculation. This prediction is consistent with the dissolution behavior of AAILs.

Full text of DOI:10.1016/j.molliq.2016.11.071

Research on solubility and bio-solubility of amino acids ionic liquids
Tian Tian, Xiaoling Hu, Ping Guan, Xiaoqi Ding
PII:
DOI:
Reference:
S0167-7322(16)33132-4
doi:10.1016/j.molliq.2016.11.071
MOLLIQ 6618
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Journal of Molecular Liquids
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Accepted date:
12 October 2016
15 November 2016
Please cite this article as: Tian Tian, Xiaoling Hu, Ping Guan, Xiaoqi Ding, Research
on solubility and bio-solubility of amino acids ionic liquids, Journal of Molecular Liquids
(2016), doi:10.1016/j.molliq.2016.11.071
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ACCEPTED MANUSCRIPT
Research on Solubility and Bio-solubility of Amino
Acids Ionic Liquids
Tian Tian, Xiaoling Hu, Ping Guan and Xiaoqi Ding
School of Natural and Applied Science, Northwestern Polytechnical University, the
Key Laboratory of Space Applied Physics and Chemistry, Ministry of Education,
Xi’an 710072, China
Abstract: Herein, the synthesis of L-(+)-α-(positive butyl)-leucine ethyl ester ionic
-
liquids with anions based on bromide (Br-), terafluoroborate (BF4 ) and
-
hexafluorophosphate (PF6 ) were presented. The structures and purities of these amino
acids ionic liquids (AAILs) were characterized by 1H NMR and the determinations of
water content. The interaction energies of AAILs-solvents/amino acids and dipole
moment of AAILs were obtained through ab initio at MP2/6-311G++(2d, p). The
relationships between the solubility of AAILs and common solvents, molecular
structure and the interaction energies of AAILs-solvents along with the influences of
temperature and molecular structure on the bio-solubility of AAILs were discussed
systematically. The results revealed that the solubility of the title AAILs increased
firstly and then decreased with decreasing dielectric constant of solvent; With the
dipole moment of AAILs and hydrogen bond interaction increasing, the solubility in
polar solvents had a increasing trend; With the interaction energies of AAILs-solvents
becoming bigger, AAILs can be easily dissolved in the solvents; The dissolution of
amino acids in AAILs was largened with temperature increasing. Additional, the ease
or difficulty of dissolution for amino acids in AAILs can be predicted by theoretical
calculation. This prediction is consistent with the dissolution behavior of AAILs.
Keywords: amino acids ionic liquids; ab initio; interaction energies; solubility;
bio-solubility
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Introduction
o
Ionic liquids (ILs) are organic salts which are less than 300 C and entirely
composed of cations and anions.1 The ionic character implies that the
physicochemical properties can be tailored virtually at will by varying their cations,
substituents, and anions.2 ILs have the unique physicochemical properties including
the extraordinary high ion density, negligible vapor pressure, high ionic conductivity,
and wide range of solubility. 3-4 In addition, as good solvents, ILs can dissolve many
organic, inorganic, metal, and polymeric compounds, etc. Due to their excellent
physicochemical properties, especially the good solubility, ILs being a new kind of
solvents have been used in the chemical community for green chemistry such as
solvents, surfactant, catalysts, etc. 5-12
In recent years, with the development of the synthesis technology of ILs and much
attention being paid to the environmental issues,13-14 discovery and synthesis of
environment-friendly ILs are particular and important. Used as novel green ILs,
amino acid ionic liquids (AAILs) provide a great opportunity to replace these
commonly used ILs. In contrast with the common ILs, AAILs are completely green
and environmental, not only due to the naturally occurring raw materials but also the
biodegradable final products.15 In addition, AAILs possess such features as bioactivity,
low toxicity and reusability.16-18 AAILs also have excellent biocompatibility and
solubility which are conducive to be dissolved in organic solvents and dissolve most
of the biological substance.19-23 Owing to these features, studies of solubility for
various chemicals with AAILs are highly important in order to evaluate and realize
proposals for applications of AAILs such as chiral synthesis, chiral separation, chiral
catalysis, fluid lubricants, and various other solvent applications.24-29 Therefore, the
significance of investigating AAILs is a particularly promising field of research
pioneered by many scholars.
Because of the property of AAILs to be dissolved in organic solvents and to
dissolve biological molecules, the interactions between AAILs and organic solvents
(and biological molecules) have been concerned. Therefore, it is necessary to
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investigate the relationships between the solvent-solute interaction and microstructure
and macroproperties of AAILs.30-32 However, previous studies mainly have been done
on the qualitative analysis of the solubility of AAILs in common solvents and little
attention was paid to the quantitative analysis of their solubility and the general law of
33-34
solubility;
Moreover, because of the structural designability and functional
diversity of AAILs, and the structure complexity and many types of biological
molecules, few studies have investigated the detailed analysis of bio-solubility for
AAILs. 35-36
Additional, quantum chemical calculation is a very effective method to study micro
structure, interactions and properties of ILs, 37-38 which provide some theoretical basis
for the solubility analysis. According to the research of Amstrong, etc, 39 AAILs could
dissolve solutes through a variety of forces mainly including dipole effect, π-π of
imidazole ring, hydrogen bonding, etc. Thus, the investigation of interactions between
AAILs and common solvents or amino acids (AAs) has a significance of guidance to
study solubility. Then, it adopts a method that the experiment is combined with
theoretical calculation to research the properties of AAILs.
In this study, L-(+)-α-(positive butyl)-leucine ethyl ester ILs based on bromide
-
-
(Br-), terafluoroborate (BF4 ) and hexafluorophosphate (PF6 ) with nine representative
common solvents and four different AAs-alanine (Ala), lysine (Lys), asparagine (Asn)
and tryptophan (Trp) all depicted in Figure 1 were selected to carry out the research
on bio-solubility. Here, ab initio at MP2/6-311G++(2d, p) was carried out using the
Gaussian 2003 software to obtain the interaction energies of AAILs-solvents/AAs and
dipole moment of AAILs. The relationships between the solubility of AAILs and
common solvents, molecular structure and the interaction energies of AAILs-solvents
along with the influences of temperature and molecular structure on the bio-solubility
of AAILs were discussed systematically. Furthermore, the dissolution properties of
AAs in AAILs could be predicted by theoretical simulation.
Experimental
Materials. Butyl bromide (w >99.0%), L-leucine (w >99.0%), ethanol (w >99.0%)
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and acetic ether (w >99.5%) were supplied by Aladdin; All chemicals were analytical
grade and used without further purification. Fluorophosphate (w >98.0%) and sodium
flulborate (w >98.0%) were provided by Alfa and recrystallized before use. They were
summarized in Table 1.
1
Measurement. H NMR spectra were recorded on a Bruker Advance 300 MHz
spectrometer with CDCl3 as solvent and tetramethylsilane as an internal standard. The
determinations of water content were obtained by Karl-Fischer titration method.
The solubility in different solvents for the synthesized AAILs was performed on
electrical conductivity meter DDS-307 (DJS-1C platinum black electrode) in
combination with analytic balance FA2004N at T = 293 K. 10 g solvent was placed in
a flask equipped with the electrical conductivity meter. A certain amount of AAIL was
added dropwise to the flask by the constant pressure dropping funnel until the
electrical conductivity was constant. The solubility was obtained through weighting
the quality of AAIL. The solvents were water, methanol, ethanol, acetone, ethyl
acetate, chloroform, methylbenzene, tetrachloromethane and cyclohexane and
exhibited in Table 1.
The bio-solubility in the synthesized AAILs for different AAs can be investigated
at T = (333-363) K. 1 g AAIL was placed in a closed flask. 0.01 g AA wasn’t added
to the flask until heated to the required temperature. The condition of dissolving the
AA was observed at the constant temperature for 6 h. This process was repeated at the
given temperature measurement point until the AA was completely dissolved. The
AAs were Ala, Lys, Asn and Trp and represented in Table 1.
Synthesis of L-leucine ethyl ester. A certain amount of thionyl chloride was added
dropwise to dehydrated alcohol (30 mL) at 268 K. Heated up to 293 K after being
stirred for 1 h and then L-leucine (1.3 g, 10 mmol) was mixed in the solution at 353 K
for 1 h. The reaction solution was distilled under reduced pressure to remove
unreacted reactant and then crystallized from triethylamine and dichloromethane
successively. After being dried in vacuum, L-leucine ethyl ester was obtained and
diplayed in Table 1.
Synthesis of L-(+)-α-(positive butyl)-leucine ethyl ester ionic liquids. L-leucine
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ethyl ester (1.6 g, 10 mmol) and butyl bromide (14.2 mL, 90 mmol) was fixed in a
microwave reactor. After vigorous shaking for 2 min, the mixture was microwave
heated at 189 W for 40 s, and then cooled to room temperature naturally. This process
was repeated for 10 times until the mixture was translucent. The reaction solution was
washed with acetic ether to remove unreacted reactant and concentrated by rotary
evaporator to obtain L-(+)-α-(positive butyl)-leucine ethyl ester bromination (AAIL1)
as a yellow sticky liquid at 303 K (Scheme 1a). AAIL1 (2.97 g, 10 mmol), sodium
flulborate (1.1 g, 10 mmol) and acetone (30 mL) was placed in a ultrasonic reactor
with 40 KHZ for 4 h. Then the unreacted AAIL1 and sodium flulborate were removed
by filter. The filter liquor was concentrated under reduced pressure to gain
L-(+)-α-(positive butyl)-leucine ethyl ester terafluoroborate (AAIL2) as a yellow
sticky liquid (Scheme 1b). AAIL1 (2.97 g, 10 mmol) and fluorophosphates (1.84 g, 10
mmol) sufficiently dissolved in water was placed in the ultrasonic reactor with 40
KHZ for 3 h. L-(+)-α-(positive butyl)-leucine ethyl ester hexafluorophosphate
(AAIL3) as a yellow oily liquid was separated from the bottom and dried under
vacuum (Scheme 1c). The synthesized AAILs made a summing up of Table 1.
Calculation methods. Due to the interaction energies of AAILs-solvents/AAs
interaction systems being mainly van der Waals and hydrogen bonding interaction, the
MP2/6-311G++(2d, p) basis set was employed for the geometry optimization. MP2 is
relatively more accurate to predict these weak interactions than density function
theory (DFT). This is because DFT may not be able to offer sound and reliable
predictive capabilities when it comes to describing systems dominated by very weak
van der Waals forces (the dispersion forces have not been taken into account for the
15
DFT calculation). No restrictions were imposed on the initial structure. Therefore,
all the geometry optimization for the minim configuration was with all degrees of
freedom. Frequency analyses of all stationary points have been performed to
guarantee the stable geometry of the configurations to be found. Interaction energy is
defined as the difference between the energy of the appointed fragment and the sum
of the energies of its free fragments. The AAILs, solvents, AAs, AAILs-solvents and
AAILs-AAs systems were optimized fully by using the MP2/6-311G++(2d, p) basis
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set, and then their energies (E, hartree) and the dipole moment of the synthesized
AAILs were determined. The results were means of 5 tests. The interaction energies
(ΔE) of the AAILs-solvents/AAs interaction systems can be evaluated by using the
following Eq.(1) 40:
E(kJ mol1)  2625.5[EAB (au) EA(au) EB (au)]
(1)
Where EA-B, EA and EB are the energy of A-B, A and B, respectively. The interaction
energy is corrected by the basis set superposition errors (BSSE) correction with the
counterpoise procedure method. 40 Zero-point energy (ZPE) correction is also used for
the total interaction energy calculations of the AAILs-solvents/AAs systems.
Results and discussion
Characterization. In order to research the solubility of the above-synthesized
AAILs, the structure and purity were investigated by 1H NMR and the determinations
1
of water content. As can be seen from the data of H-NMR for the AAILs in Table 2,
the synthetic compounds have verified to be the synthesized AAILs. The symbol,
abbreviation, water content and yield of the above-synthesized AAILs were showed in
Table 3. Based on the results of 1H NMR and water content, the range of the purity of
AAILs can be determined. The mass fraction purity is > 98.0%. The results
manifested that these AAILs could be used to research the solubility and
bio-solubility.
Solubility of AAILs in common solvent. The satisfactory solubility of AAILs
determines their applications in organic synthesis, extraction separation, etc. The
solubility is powerfully relied on the structures of AAILs and one of the important
physicochemical properties of AAILs whose value is concerned with solvents, the
structure of cation and anion, etc. Table 4 provided the test results of the solubility in
different solvents for the AAILs at 293 K. The solubility of the AAILs with nine
solvents mostly abided by the similarity-intermiscibility theory. However, the
solubility of different AAILs with the same solvents had enormous difference because
of their individual structures. So it is of great importance to understand the general
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law of solubility for these AAILs, in order to extend the development and application
of AAILs. Therefore, the law of solubility for the AAILs is being further investigated
and the relationships between the solubility and molecular structure, common solvents,
and the interaction energies between solvents and solute molecules were discussed
systematically in the following.
Relationship between Solubility and Solvents. Dielectric constant of solvent is an
important property that represents the capacity to dissolve solute. If dielectric constant
of solvent is bigger, it will have a stronger ability to dissolve polar solute. As far as
the same AAIL, with the dielectric constant of solvent increasing, the solubility of the
AAIL improved. According to the data of Table 4 to obtain Figure 1a in the
supporting information, it showed that the solubility of AAILs increased firstly and
decreased later as the dielectric constant of solvents increased, which for the AAILs
was best in ethanol. Water, methanol and ethanol as polar protic solvents could
provide proton and possess the stronger hydrogen bond interaction with AAILs. In
addition, acetone as polar aprotic solvent, the interaction forces between Br- or F- and
methyl cation of acetone should form hydrogen bonds (C-H…F or C-H…Br) to make
AAILs easily dissolved in acetone; 41 The methyl cation connected on the carbonyl of
acetone was electron-donating group and possessed a great deal of activity, which
made the interaction forces between AAILs and acetone enhanced. Ethyl acetate as
nonpolar solvent had similar structure (C-H…C=Oδ-) with acetone. Moreover
chloroform as nonpolar solvent could form hydrogen bonds (C-H…Cl). So AAILs
had a good solubility in polar protic solvents and polar aprotic solvents. There were
hydrophobic interactions between the AAILs and nonpolar solvents ( methylbenzene,
tetrachloromethane and cyclohexane), which made nonpolar solvents difficultly to
dissolve AAILs; Therefore, AAILs were undissolved or insoluble in these nonpolar
solvents. The analysis results were in agreement with experimental results (Figure
1a).
Relationship between Solubility and Interaction Energy. The dissolution
mechanism of small molecular compound is that between solvents and solute
molecules there is an attraction which can destroy the interaction force between solute
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molecules and gradually cause the solute molecules off the surface of solute, and then
the solute molecules uniformly disperse to the solvents by diffusion.34 The interaction
energies between solvents and solute molecules can describe the balance of the two
forces, Van der Wals forces and Hydrogen bonding interaction, which have direct
influence on the solubility of AAILs. In most cases, AAILs as polar phases with
solubility can be considered being mainly determined by the ability of the salt to act a
hydrogen-bond donors/acceptors and the degree of localization of the charges on the
anions. Thus the ability of solutes to form hydrogen bonds or other possible
interactions with potential solvents is an important feature of its behavior. The
interaction energies and their corrected values of BSSE and ZPE of AAILs-solvents
systems were gave in Table 5. It showed that the interaction energies of
AAILs-solvents increased firstly and decreased later as the dielectric constant of
solvents increased, which for AAIL-ethanol was biggest. The AAILs diffused to the
solvents has got easier with the interaction energies of AAIL-solvent turning higher;
namely the solubility of AAILs increased firstly and decreased later, which for the
AAILs was best in ethanol. In other words, AAILs were such good hydrogen-bond
donors/acceptors because they were charged; Methanol, ethanol, acetone, ethyl
acetate and chloroform used in this work were also good hydrogen-bond acceptors but
not as well as AAILs. Additional, the interaction energies between AAILs and
nonpolar solvents except ethyl acetate were small, even some were positive, so the
AAILs were undissolved or insoluble in these nonpolar solvents. The interaction
energies between AAILs and ethyl acetate were big and thus AAILs had a good
solubility in ethyl acetate. Above all, the theoretical analysis was in basic conformity
with experimental results (Figure 1a).
Relationship between Solubility and Structure. The solubility of different AAILs
with the same solvents had been enormously different owing to their individual
structure; Hence the relationship between the solubility and molecular structure of
AAILs was investigated. As seen in Figure 2a in the supporting information with data
from Table 4, it was easy to observe that the solubility in polar solvents (methanol and
ethanol) was SAAIL3> SAAIL2 > SAAIL1 and in polar aprotic solvents (acetone, ethyl
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acetate and chloroform) and nonpolar solvents ( methylbenzene, tetrachloromethane
and cyclohexane) was SAAIL1> SAAIL2 > SAAIL3. From the anionic point of view, because
of [PF6]- and [BF4]- anion having large number of F-, it was easier for AAIL2 and
AAIL3 than AAIL1 containing Br- anion to form hydrogen bond interaction with
methanol and ethanol. Then the [PF6]- and [BF4]- anion had larger number of electrons
outside the nucleus, bigger atomic radius and weaker control ability of outer electron
than Br-, so it was susceptible to the effect of electric field and then the electron cloud
deformation produced polarization effect, which leaded to the larger electron cloud
offset. From the interaction energies of AAILs-solvents of view (Table 5), that
between AAIL3 and polar protic solvents (methanol and ethanol) were biggest, which
made the AAIL3 easier diffusing to the polar solvents than AAIL1 and AAIL2.
Additional, the bond-types of organic solvents were polar covalent bonds. But ethyl
acetate, chloroform, methylbenzene, tetrachloromethane and cyclohexane possessing
polar covalent bonds were also nonpolar solvents. That was all electrons distributed in
molecule on average, which led to the nonpolar solvents difficultly formed
interactions with AAILs. Furthermore, the interaction energies obtained from the
calculation by MP2/6-311G++(2d, p) between them were indeed small. Finally, the
relationship between the solvent molecular structure and bonding types presence
with the impact on interaction energy thus ultimately affected the dissolution ability
of the solvent. However, the solubility in water was SAAIL1> SAAIL2 > SAAIL3. This was
because Br- and [BF4]- were hydrophilic and [PF6]- were hydrophobic. Through
theoretical calculation of the interaction energies in Table 5, the anions had formed
strong hydrogen bond interaction with water but the strength of hydrogen bond
interaction with water for these anions was [PF6]- > [BF4]- >Br-. Although, the
hydrophilic effect was stronger than hydrogen bonding interaction; So the solubility
in water was indeed SAAIL1> SAAIL2 > SAAIL3. In addition, dipole moment of molecule
had a certain relationship with polarity, solubility, and other physical properties. The
dipole moment showed in Table 6 of the AAILs increased, which cause that the nature
of polarity of AAILs increasing; Thus, the polarity was AAIL3> AAIL2>AAIL1.
Bio-solubility of AAILs for AAs
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Influence of temperature on bio-solubility. The dissolution process is that solute
molecules uniformly disperse to solvents by diffusion. Furthermore, Gibbs free
energy can determine the direction of the dissolution process; that is to say if the
Gibbs free energy changes of mixing ΔGM < 0 [Eq. (2)], this process can be
spontaneously happened.
GM  HM T SM  0
(2)
Where ΔHM is the mixing enthalpy, ΔSM is the mixing entropy and T is the
solution temperature. The arrangement of molecules tends to chaos in the dissolution
process; Thus enthalpy change on the mixing of AAs and AAILs always increases
(ΔSM > 0), namely the higher temperature is beneficial to dissolve AAs. Within the
temperature investigated during this study, the bio-solubility of the synthesized
AAILs for four amino acids was explored at T= (333 to 363) K as could be seen from
Table 1a in the supporting information. It showed that 0.01 g AAs completely
dissolved in 1 g AAILs needed a higher temperature than room temperature. When
raising temperature, the thermal motion of ions of the AAILs could be aggravated, the
molecular kinetic energy of liquid increased, and the interatomic and intermolecular
forces of AAILs decreased; Moreover, the interaction between the contacting surface
of the AAs and ions of the AAILs in the process of dissolution increased. Finally the
higher temperature can provide more energies and the dissolution was also facilitated.
Influence of structure of AAs on bio-solubility. AAILs have excellent solubility
which are conducive to dissolve most of biological substance, such as AAs. Four AAs
(Ala, Lys, Asn and Trp) were selected to carry out the research on bio-solubility. So
the relationship between the bio-solubility and molecular structure of AAs was
investigated. Figure 2 derived from Table 1a represented the completely dissolved
temperature of the four amino acids in the synthesized AAILs. It showed that the AAs
completely dissolved in the AAILs needed a higher temperature than room
temperature and the ease to complexity of dissolution for the four AAs was
Lys>Ala>Trp>Asn. According to the relationship R-group of AAs and water, it can be
divided into polar AAs and nonpolar AAs and the synthesized AAILs were
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hydrophilic ionic liquids through the investigation on the solubility of AAILs in
common solvents (Table 4). Lys as polar AAs, due to the introduction of one more
-NH2 (Figure 1), it had the strongest hydrogen bond interaction with AAILs and most
hydrophilic in the four AAs. In addition, electrostatic attraction existed between Lys
and AAILs because of Lys positively charging and the negative charged on the anions
of AAILs. Thus Lys had the best solubility in the AAILs. Although Asn as polar and
hydrophilic solute, it had the worst solubility in AAILs; Because Asn can form the
intramolecular hydrogen bond according to the structure in Figure 1, the capability of
accepting protons for the carbonyl oxygen (C=Oδ-) was reduced and the hydrogen
bond interaction with AAILs has been weakened. Ala and Trp were nonpolar AAs and
Ala possessed less hydrophobic than Trp. The stronger the hydrophobicity of nonpolar
AAs, the more difficult AAs dissolved in the AAILs. The analysis result was in
agreement with experimental results (Figure 2).
Influence of structure of AAILs on bio-solubility. There was a difference in
bio-solubility of the different AAILs for the same AA due to the different structure of
anions of AAILs; Thus the relationship between the bio-solubility and molecular
structure of AAILs was researched. As seen from Figure 2, it was easy to observe that
the dissolution ability for AAILs to dissolve AAs was AAIL3> AAIL2 > AAIL1. For
Lys and Asn, under the identical cation, the same analysis with the influence of the
structure of anions on solubility for AAILs in common solvents, the anions of AAIL2
and AAIL3 had larger number of electrons outside the nucleus, bigger atomic radius
and weaker control ability of outer electron than Br-, therefore it was susceptible to
the effect of electric field and then the electron cloud deformation produced
polarization effect, which leaded to the bigger polarity. In addition, the dipole moment
of AAILs was AAIL3> AAIL2>AAIL1 showed in Table 6, which cause that the
nature of polarity of AAILs increased; Hence, the AAILs dissloving Lys and Asn
increased. For Ala and Trp, the dissolution ability for AAILs to dissolve them was
also AAIL3> AAIL2 > AAIL1. Because it was easier for AAIL3 and AAIL2 having
large number of F- to form hydrogen bond interaction with them and the interaction
had more important effect on dissolution than polarization. From the interaction
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energies of the AAILs-AAs of view, the interaction energies and their corrected values
of BSSE and ZPE for AAILs-AAs systems were gave in Table 7. It obviously realized
that the interaction energies of AAIL3-AA were biggest, that is to say the hydrogen
bond interaction of AAIL3 with AAs in the three AAILs was greatest. The
above-analyzed process illustrates that the interaction energies can be used to discuss
the dissolution ability for AAILs to dissolve AAs.
Theoretical and practical analysis of bio-solubility. The mechanism of dissolution
for low molecular weight compounds is that between solvents and solutes there is an
attraction which can destroy the intermolecular forces between solutes. 19 With the
interaction energy between solute and solvent molecules becoming greater, the solutes
easily diffused to the solvents. As can be seen from the data of the interaction energies
of AAILs-AAs in Table 7, and compared with the practical bio-solubility, the ease
or complexity of dissolution for the four AAs in the synthesized AAILs and that of
dissolution ability of AAILs for the four AAs can be theoretically estimated in Table 8
and Table 9 respectively. “Theoretical” was the sequence of dissolution ability for the
calculation made using the method and “Practical” was that based on experimental
work. It showed that the theoretical predictions were consistent with the experimental
results except Asn (Table 8). Asn can easily form intramolecular hydrogen bond
which made the capability of accepting protons for the carbonyl oxygen (C=Oδ-)
reduced and the hydrogen bond interaction with AAILs weakened. Although the
theoretical predictions with the experimental results had a certain deviation; The
theoretical prediction still had a significance of guidance to study the interactions
between AAILs and other biological molecules.
Conclusions
L-(+)-α-(positive butyl)-leucine ethyl ester chiral ionic liquids with anions based on
-
-
bromide (Br-), terafluoroborate (BF4 ) and hexafluorophosphate (PF6 ) were
synthesized. The quantitative solubility of the synthesized AAILs in common solvents
were determined at 293 K and the qualitative solubility of AAs in the AAILs were
investigated at T= (333 to 363) K. The interaction energies of the AAILs-solvents
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/AAs interaction systems were obtained by using MP2/6-311G++ (2d, p) basis set.
We can obtain these conclusion: (1)The solubility of the AAILs increased firstly and
then decreased with decreasing dielectric constant of solvent; (2) With the dipole
moment of AAILs and hydrogen bond interaction increased, the solubility in polar
solvents had a increasing trend. (3) The AAILs could easily diffuse into the solvents
with the interaction energy of AAILs-solvents becoming bigger. (4) The higher
temperature, the bigger dissolution of AAs in AAILs. (5) AAs are easy to dissolve in
AAILs and the ease to complexity of dissolution for the four AAs is
Lys>Ala>Trp>Asn. (6) Additional, the ease or complexity of dissolution for AAs in
the AAILs can be predicted by using ab initio at MP2/6-311G++ (2d, p) level. This
prediction is consistent with the bio-solubility of AAILs.
Corresponding Author
* Tel./Fax: +86 29 88431639. E-mail: tiantian19860102@126.com.
Acknowledgements
The authors are grateful for the financial support provided by the Special Funds
of the National Natural Science Foundation of China (Grant No. 51433008).
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Ala
Asn
Lys
Trp
Figure 1. Structure of the four AAs studied in this study
17

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Table 1. Chemical Sample Table
Chemical
name
Initial mass
fraction purity
>99.0%
>99.0%
-
Purification
method
none
Final mass
Analysis
Source
Aladdin
Aladdin
Alfa
fraction purity
method
1-bromobutane
L-leucine
fluorophosphate
sodium flulborate
water
-
-
none
-
-
recrystallized
recrystallized
distillation
none
>98.0%
-
Alfa
-
>98.0%
-
Self made
Aladdin
Aladdin
Aladdin
Aladdin
Aladdin
Aladdin
Aladdin
Aladdin
Aladdin
Aladdin
Aladdin
Aladdin
synthesis
synthesis
synthesis
-
>99.5%
conductometry
methanol
ethanol
>99.5%
>99.5%
>99.5%
>99.5%
>99.5%
>99.5%
>99.5%
>99.5%
>99.5%
>99.5%
>99.5%
>99.5%
-
-
-
none
-
-
acetone
none
-
-
acetic ether
chloroform
methylbenzene
tetrachloromethane
cyclohexane
Ala a
none
-
-
none
-
-
none
-
-
none
-
-
none
-
-
none
-
-
Lys b
none
-
-
Asn c
none
-
-
Trp d
none
-
-
AAIL1 e
skimming
evaporation
evaporation
>98.0%
>98.0%
>98.0%
1H-NMR
1H-NMR
1H-NMR
AAIL2 f
-
AAIL3 g
-
a Ala= Alanine
b Lys=Lysine
c Asn=L-Asnaragine
d Trp=Tryptophan
e AAIL1=L-(+)-α-(positive butyl)-leucine ethyl ester bromination
f AAIL2=L-(+)-α-(positive butyl)-leucine ethyl ester terafluoroborate
g AAIL3=L-(+)-α-(positive butyl)-leucine ethyl ester hexafluorophosphate
18

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Scheme 1. Synthetic pathway to the title AAILs
19

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Table 2. 1H-NMR data of the synthesized AAILs
IL
1H-NMR(300 MHz, CDCl3, δ / ppm)
AAIL1
AAIL2
AAIL3
0.921(m,2H),1.210(m,8H),2.952(m, 2H),3.670(m, 1H)
0.925(m,2H),1.217(m,8H),2.955(m, 2H),3.690(m, 1H)
0.928(m,2H),1.309(m,8H),2.957(m, 2H),3.710(m, 1H)
20

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Table 3. The symbol, abbreviation, water content* and yield of the title AAILs
u
Water
symbol
Magnetic ionic liquids
Abre.
Yield
(yeild)
content
0.029%
0.035%
0.038%
H-LEU-OET·Br
H-LEU-OET·BF4
H-LEU-OET·PF6
AAIL1
AAIL2
L-(+)-α-(positive butyl)-leucine ethyl ester bromination
L-(+)-α-(positive butyl)-leucine ethyl ester terafluoroborate
89.4%
85.7%
82.1%
0.4%
0.5%
0.6%
AAIL3 L-(+)-α-(positive butyl)-leucine ethyl ester hexafluorophosphate
* Standard uncertainties are u(T)=1 K, u(Water content)=0.001%.
21

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Table 4. Solubility (S)a of the title AAILs in different solvents at 293 K*(p = 0.1MPa)
Solvent
S(g/10g)
AAIL1 (l) b
AAIL2 (l)
AAIL3 (l)
IL
water
2.4851
4.8519
2.0286
5.9913
1.8002
6.1341
methanol
ethanol
acetone
5.3642
5.0320
2.2060
1.3676
0.0770
0.0312
0.0000
6.5617
5.0030
2.0710
0.9568
0.0502
0.0000
0.0000
6.8305
4.8090
1.8088
0.0680
0.0189
0.0000
0.0000
acetic ether
chloroform
methylbenzene
tetrachloromethane
cyclohexane
a The solubilities given in Table 8 means grams of solute which is in 10 grams of solvent at 293 K.
Grams of solute and solvent can be accurately weighed with analytic balance (u(m)=0.1 mg) in the
actual experiment. Through conversion, grams of solute in 10 grams of solvent (i.e., solubilities)
were obtained.
b The smbols "l" (liquid) represent the phase of the ionic liquid at 293 K.
* Standard uncertainties u are u(T)=1 K, ur(S)=0.03 for S >0.0001 g, ur(S)=0.05 for S <0.0001 g.
(ur(S)=(S*-S)/S; where S* is the experimental value of solubility, S is the average value of
solubility). For 0.0000 g in the Table, the value is ≤0.0001 g.
22

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Table 5. Interaction energies (ΔE), interaction energies that are corrected by BSSE and ZPE
(ΔEBSSE+ZPE) of AAILs-solvents at the MP2/6-311G++(2d, p) Level (kJ/mol)
AAIL1
AAIL2
AAIL3
Solvent
∆E
ΔEBSSE+ZPE
∆E
ΔEBSSE+ZPE
∆E
ΔEBSSE+ZPE
-71.7
-78.9
-86.6
-86
-55.6
-67.5
-76.5
-74.6
-45.4
-41.6
-20.8
-4.6
-74.4
-88.7
-93.6
-83.4
-50.6
-36.5
-13.6
-0.7
-59.6
-76.6
-80.6
-70.9
-39.4
-25.2
-4.7
-75.3
-90.1
-94.9
-81.6
-49.5
-14
-61.1
-80.4
-83.2
-69.7
-41.5
-5.9
water
methanol
ethanol
acetone
acetic ether
-52.7
-47.9
-27.3
-12.3
0.1
chloroform
methylbenzene
tetrachloromethane
cyclohexane
-11.2
-3.8
-4.1
4.5
4.0
5.1
3.0
8.2
9.5
19.1
*Standard uncertainties are u(∆E)=0.1 kJ/mol (u(∆E)=∆E*-∆E; where ∆E* is the calculation value
of interaction energy, ∆E is the average value of interaction energy).
23

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Table 6. Dipole moment of the title AAILs
AAILs
AAIL1
10.433
AAIL2
11.130
AAIL3
12.082
Diople moment
24

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Figure 2. Completely dissolved temperature of the four amino acids in the synthesized
AAILs
25

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Table 7. Interaction energies (ΔE), interaction energies that are corrected by BSSE and ZPE
(ΔEBSSE+ZPE) and the corrected values of BSSE and ZPE of AAILs-AAs (kJ/mol)
AAIL1
AAIL2
AAIL3
AA
∆E
ΔEBSSE+ZPE
∆E
ΔEBSSE+ZPE
∆E
ΔEBSSE+ZPE
-72.1
-69.1
-66.7
-65.1
-59.6
-56.4
-54.7
-51.2
-74.1
-69.4
-67.0
-66.3
-61.6
-57.7
-55.3
-53.5
-76.8
-70.5
-67.6
-66.8
-63.4
-58.6
-55.8
-55.0
Lys
Asn
Ala
Trp
*Standard uncertainties are u(∆E)=0.1 kJ/mol (u(∆E)=∆E*-∆E; where ∆E* is the calculation value
of interaction energy, ∆E is the average value of interaction energy).
26

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Table 8. Theoretical predictions and experimental results of the solubility of AAs in the
synthesized AAILs
Dissolution ability
AAILs
Theoretical
Practical
AAIL1
AAIL2
AAIL3
Lys>Asn>Ala>Trp
Lys>Asn>Ala>Trp
Lys>Asn>Ala>Trp
Lys>Ala>Trp>Asn
Lys>Ala>Trp>Asn
Lys>Ala>Trp>Asn
27

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Table 9. Theoretical predictions and experimental results of the dissolution ability of the
synthesized AAILs for AAs
Dissolution ability
AAs
Theoretical
Practical
Lys
Asn
Ala
Trp
AAIL3>AAIL2>AAIL1
AAIL3>AAIL2>AAIL1
AAIL3>AAIL2>AAIL1
AAIL3>AAIL2>AAIL1
AAIL3>AAIL2>AAIL1
AAIL3≧AAIL2>AAIL1
AAIL3≧AAIL2>AAIL1
AAIL3≧AAIL2>AAIL1
28

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For Table of Contents Only
Theoretical Study on Solubility and Bio-solubility of Amino Acids Ionic Liquids
370
360
350
340
AAIL
330
AAIL2
AAIL3
Trp
Ala
Asn
Lys
Graphical abstract
29