Investigation of Taniaphos as a chiral selector in chiral extraction of amino acid enantiomers

Article abstract of DOI:10.1002/chir.23309

Finding chiral selector with high stereoselectivity to a variety of amino acid enantiomers remains a challenge and warrants further research. In this work, Taniaphos, a chiral ligand with rotatable spatial configuration, was employed as a chiral extractant to enantioseparate various amino acid enantiomers. Phenylalanine (Phe), homophenylalanine (Hphe), 4-nitrophenylalanine (Nphe), and 3-chloro-phenylglycine (Cpheg) were used as substrates to evaluate the extraction efficiency. The results revealed that Taniaphos-Cu exhibited good abilities to enantioseparate Phe, Hphe, Nphe, and Cpheg with the highest separation factors (α) of 3.13, 2.10, 2.32, and 2.14, respectively. Taniaphos-Cu is more conducive to combine with D-amino acid in extraction. The influences of pH, Taniaphos-Cu, and concentration and extraction temperature on extraction were comprehensively evaluated. The highest performance factors (pf) for Phe, Hphe, Nphe, and Cpheg at optimal extraction conditions were 0.08892, 0.1250, 0.09621, and 0.08021, respectively. The recognition mechanism between Taniaphos-Cu and amino acid enantiomers was discussed. The coordination interaction between Taniaphos-Cu and -COO^?, π-π interaction between Taniaphos-Cu and amino acid enantiomers are important acting forces in chiral extraction. The steric-hindrance between -NH₂ and -OH lead to Taniaphos-Cu-D-Phe is more stable than Taniaphos-Cu-L-Phe. This work provided a chiral extractant that has good abilities to enantioseparate various amino acid enantiomers.

Full text of DOI:10.1002/chir.23309

Received: 7 February 2021
DOI: 10.1002/chir.23309
Revised: 10 March 2021
Accepted: 11 March 2021
R E S E A R C H A R T I C L E
Investigation of Taniaphos as a chiral selector in chiral
extraction of amino acid enantiomers
Wenjie Xiao | Shuhuan Chen | Xiong Liu
| Yu Ma
School of Chemistry and Chemical
Abstract
Engineering, Hunan University of Science
and Technology, Xiangtan, Hunan, China
Finding chiral selector with high stereoselectivity to a variety of amino acid
enantiomers remains a challenge and warrants further research. In this work,
Taniaphos, a chiral ligand with rotatable spatial configuration, was employed
as a chiral extractant to enantioseparate various amino acid enantiomers.
Phenylalanine (Phe), homophenylalanine (Hphe), 4-nitrophenylalanine
Correspondence
Xiong Liu, School of Chemistry and
Chemical Engineering, Hunan University
of Science and Technology, Xiangtan,
Hunan 411201, China.
(Nphe), and 3-chloro-phenylglycine (Cpheg) were used as substrates to evalu-
Email: liuxiongcsu@163.com
ate the extraction efficiency. The results revealed that Taniaphos-Cu exhibited
good abilities to enantioseparate Phe, Hphe, Nphe, and Cpheg with the highest
separation factors (α) of 3.13, 2.10, 2.32, and 2.14, respectively. Taniaphos-Cu
is more conducive to combine with D-amino acid in extraction. The influences
of pH, Taniaphos-Cu, and concentration and extraction temperature on extrac-
tion were comprehensively evaluated. The highest performance factors (pf) for
Phe, Hphe, Nphe, and Cpheg at optimal extraction conditions were 0.08892,
Funding information
National Natural Science Foundation of
China, Grant/Award Number: 51703060
0.1250, 0.09621, and 0.08021, respectively. The recognition mechanism
between Taniaphos-Cu and amino acid enantiomers was discussed. The coor-
−
dination interaction between Taniaphos-Cu and COO , π-π interaction
between Taniaphos-Cu and amino acid enantiomers are important acting
forces in chiral extraction. The steric-hindrance between NH and OH lead
2
to Taniaphos-Cu-D-Phe is more stable than Taniaphos-Cu-L-Phe. This work
provided a chiral extractant that has good abilities to enantioseparate various
amino acid enantiomers.
K E Y W O R D S
amino acid enantiomers, chiral extraction, recognition mechanism, Taniaphos
2
1
| INTRODUCTION
ofloxacin. Consequently, much effort had been made to
3
–6
obtain optically pure enantiomers in the past decades.
Enantiomers are chiral molecules that are non-
superimposable mirror images of each other. In general,
one enantiomer of chiral drugs is safe and effective, while
Asymmetric synthesis, raceme separation, and isolation
from natural sources are the main pathway to prepare
pure enantiomers. Isolation of enantiomers from natural
sources is not broadly used because of its low yield and
the limited types of enantiomers. Thus, asymmetric
synthesis and raceme separation are the most promising
methods to obtain pure enantiomers. And numerous
1
the other is maybe ineffective or even toxic. There are
many examples of chiral medicines whose enantiomers
vary drastically in their properties. For instance, the anti-
microbial activity of (S)-ofloxacin is 9.3 times that of (R)-
292
© 2021 Wiley Periodicals LLC.
wileyonlinelibrary.com/journal/chir
Chirality. 2021;33:292–302.

XIAO ET AL.
293
efforts have been made in the past several decades to
develop efficient chiral catalysts and selectors. For
instance, BINAP was discovered by Miyashita et al. And
showed good ability to separate 4-Nitrophenylalanine
enantiomers, and (S, S)-DIOP only showed good ability
to separate 3-chloro-phenylglycine enantiomers. These
features bring inspiration to us that chiral ligand with
rotatable spatial configuration may be a versatile host in
separation of an entire class of racemates.
7
this ligand has been successfully applied in asymmetric
8,9
catalysis with high efficiency and economic. Recently,
BINAP has also been confirmed to be an efficient chiral
selector in the enantioseparation of racemic amino acids.
Taniaphos((SP)-1-[(S)-α-(Dimethylamino)-2-(diph-
enylphosphino)benzyl]-2-diphenylphosphinoferrocene) is
10
Verkuijl et al. reported that BINAP-Pd was a good
chiral selector in enantioseparation of tryptophan with
a famous Ferrocene ligand that is often used as catalyst
11,12
13
18,19
separation factor (α) of 2.4. Tang et al.
and Liu et al.
in asymmetric synthesis.
The chemical structure of
also reported that BINAP-Cu complex was a good
chiral selector for enantioseparation of phenylalanine,
phenylglycine, and 4-Nitrophenylalanine with separation
factor (α) of 5.20, 2.15, and 3.37, respectively. Further-
more, the enantioseparation abilities of several BINAP
derivatives had also been detected in our previous work.
The results indicated that BINAP derivatives, such as (S)-
SEGPHOS and (S)-MeO-BIPHEP, have good separation
Taniaphos is shown in Figure 1. Compared with BINAP,
MeO-BIPHEP, and SEGPHOS, benzene rings in
Taniaphos also can rotate properly. Accordingly, we
hypothesized that Taniaphos might be another chiral
diphosphine ligand that has considerable abilities to
enantioseparate various racemic amino acids. In this
work, Taniaphos metal was applied as chiral extractant
in chiral extraction for the first time. Phenylalanine
(Phe), homophenylalanine (Hphe), 4-nitrophenylalanine
(Nphe), and 3-chloro-phenylglycine (Cpheg) were used
as substrates to evaluate the enantioselectivity of
Taniaphos metal. The influences of metal precursor,
organic solvent, pH, extractant concentration, and extrac-
tion temperature on extraction efficiency were investi-
gated. Also, the possible recognition mechanism had
been discussed.
14,15
capabilities toward amino acid enantiomers.
More
importantly, some other chiral diphosphine ligands used
in asymmetric catalytic also exhibited considerable abili-
ties to enantioseparate racemic amino acids. For instance,
(
3
S, S)-DIOP is a proper extractant to enantioseparate
-chloro-phenylglycine enantiomers with α of 1.84.
16
(
S)-SDP is a spiro ligand that could be used as chiral
selector in chiral extraction of 4-Nitrophenylalanine with
17
α of 3.32. However, all these non-biphenyl (bin-
aphthalene) diphosphine ligands only showed separation
ability to one kind of amino acid enantiomers. Finding
chiral selector with high stereoselectivity to a variety of
amino acid enantiomers remains a challenge and war-
rants further research.
2 | MATERIALS AND METHODS
2.1 | Materials and reagents
As shown in Figure 1, it is obvious that the benzene
rings in the chemical structures of BINAP, MeO-BIPHEP,
and SEGPHOS can rotate properly. Thus, these types of
chiral extractants could enantioseparate various amino
acid enantiomers by adjusting their stereochemical
structures. However, (S)-SDP and (S, S)-DIOP are con-
formationally rigid ligands. Consequently, (S)-SDP only
Taniaphos (>99%) was purchased from Bide Pharmatech
Ltd. Amino acid enantiomers and racemates were
purchase from Adamas Reagent Co, Ltd. Metal precur-
sors, such as [(CH CN) Cu]PF (>98%), (CH CN) PdCl
2
3
4
6
3
2
(>99%) and [(C H ) P] NiCl (>98%), were purchased
6
5 3
2
2
from J&K Scientific Ltd. Organic solvents (analytic grade)
and inorganic salts (analytic grade) were purchased from
Adamas Reagent Co, Ltd.
2.2 | Extraction of amino acid
enantiomers
The organic phase was prepared as follows. Briefly,
Taniaphos (0.1 mmol) and metal precursor (0.1 mmol)
were dissolved in 100 ml organic solvent. After mixed for
12 h, the Taniaphos-metal complex was obtained with a
concentration of 1.0 mmol/L. The water phase was
prepared as follows. Briefly, amino acid racemates
(0.2 mmol) were dissolved in 100 ml PBS solution
(pH = 5–12) with concentration of 2.0 mmol/L.
FIGURE 1 Chiral diphosphine ligands investigated in previous
work and this work

294
XIAO ET AL.
Extraction of amino acid enantiomers was carried out as
follows. Briefly, 2.0 ml Taniaphos-metal solution and
2.4 | OPTIMIZATION OF EXTRACTION
PROCESS
2
.0 ml amino acid racemates were placed in a 10 ml cen-
trifuge tube. The organic phase and water phase were
shaken for 12 h at 120 rpm by a constant temperature
shaker. Then, the extraction system stood for 12 h to
make organic-water phases stratified. The water phase
was filtered by a 0.45 μm filter membrane. The obtained
filtrate was then analyzed by the HPLC method described
In this work, the extraction conditions were optimized
through single-factor test and Response Surface Method-
ology. Based on the results obtained in single-factor
experiments, the optimal conditions for extraction of
amino acid enantiomers by Taniaphos-Cu were investi-
gated with a central composite design (CCD). There were
13 runs carried out in CCD. The extraction models were
obtained by a quadratic polynomial stepwise regression
method. And the mathematical model can be given as
Equation 7.
14,15
in our previous work.
2.3 | Calculations
2
2
Distribution coefficient is defined as the ratio of the total
concentration of solute in the organic phase to the total
concentration of solute in the aqueous phase. The distri-
bution coefficients of L- and D-amino acid in extraction
were calculated by Equations 1 and 2, respectively. CL,org
and CD,org represent L- and D-amino acid in organic
phase after extraction. CL,w and CD,w represent L- and D-
amino acid in water phase after extraction. Separation
factor (α) can be employed to evaluate the degree of sepa-
ration of L- and D-amino acid in single-stage extraction.
And it could be calculated by Equation 3. In chiral
extraction, the purity of enantiomer is an important indi-
cator to evaluate the enantioselectivity of chiral
extractant. The enantiomeric excess (ee) of amino acid
enantiomers in organic phase was calculated by Equa-
tion 4. Fraction of enantiomer (f) is defined as the rate of
substance that is extracted into the organic phase. It is
often adopted to evaluate the yield of extraction. Fraction
of enantiomer (f) can be calculated by Equation 5. Perfor-
mance factor (pf) is always used to comprehensively eval-
uate the efficiency of enantioseparation. High value of pf
implied that enantiomers are extracted with high purity
and high yield simultaneously. The value of pf can be cal-
pf = b + b A + b B + b AB + b A + b B ,
ð7Þ
0
1
2
12
11
22
where pf is response, A is pH of water phase, B is
Taniaphos-Cu concentration, b is intercept, b and b are
0
1
2
linear, b11 and b22 are quadratic, and b is interaction
12
22
regression coefficient term.
3 | RESULTS AND DISCUSSION
3.1 | Extraction of amino acid
enantiomers using different Taniaphos-
metal complexes
In extraction, Taniaphos ligand should combine with
metal ions to form an organometallic complex that has
the ability to recognize amino acid enantiomers.
According to previous reports, Cu(I), Pd (II), and Ni
(II) are always used as metal precursors in chiral
12,23
extraction of racemic amino acids.
Thus, the
enantioselectivities of Taniaphos-Cu, Taniaphos-Pd, and
Taniaphos-Ni had been detected, and the results were
tabulated in Table 1. Obviously, Taniaphos-Ni showed lit-
tle ability to recognize all racemic amino acids with α
values were all below 1.20. Taniaphos-Pd exhibited mod-
erate abilities to enantioseparate Phe, Hphe, Nphe, and
Cpheg with α values were 1.26, 1.10, 1.61, and 1.44,
respectively. Taniaphos-Cu showed the highest abilities
to enantioseparate Phe, Hphe, Nphe, and Cpheg with α
values were 2.17, 1.28, 1.81, and 1.54, respectively. Thus,
Cu(I) is the most suitable metal precursor for Taniaphos
in enantioseparation. The enantioselectivity of
Taniaphos-Cu is higher than Taniaphos-Pd. This is prob-
ably because that 4-coordinated Cu has a tetrahedral
structure while 4-coordinated Pd has a plane quadrilat-
20,21
culated according to Equation 6.
k = CL,org
CL,w,
ð1Þ
ð2Þ
ð3Þ
=
L
k = CD,org
CD,w,
=
D
α = kD
=
kL,
CD,org −CL,org
CD,org + CL,org
eeorg
=
,
ð4Þ
24,25
eral structure.
The difference of the spatial configura-
tions makes Taniaphos-Cu more efficient in chiral
extraction of amino acid enantiomers. The values of kD
were bigger than k , which indicated that D-amino acids
f = CD,org
ðCD,org + CD,wÞ,
ð5Þ
ð6Þ
=
26
pf = f × eeorg
:
L

XIAO ET AL.
295
TABLE 1 Enantioselectivities of
Taniaphos-metal complexes in chiral
extraction
a
a
a
(
CH
3
CN)
2
PdCl
2
[(CH
3
CN)
4
Cu]PF
6
6 5 3 2 2
[(C H ) P] NiCl
Amino acids
Phe
k
D
k
L
α
k
D
k
L
α
k
D
k
L
α
0.519
0.824
0.385
1.176
0.413
0.751
0.239
0.816
1.26
1.10
1.61
1.44
0.254
1.701
0.220
0.553
0.117
1.325
0.121
0.358
2.17
1.28
1.81
1.54
0.211
0.674
0.158
0.391
0.187
0.631
0.136
0.375
1.13
1.07
1.16
1.04
Hphe
Nphe
Cpheg
a
The organic solvent is 1,2-Dichloroethane; pH is 8.0.
were the main enantiomers in organic phase after
extraction. Consequently, Taniaphos-metal complexes
tend to combine with D-amino acid enantiomers in
enantioseparation.
3.3 | Enantioselectivities of Taniaphos-
Cu at different Ph
The enantioselectivities of Taniaphos-Cu at different pH
were determined and the curves of k, α, ee, and pf were
demonstrated in Figure 2. Obviously, kD and kL were
both increased with pH of water phase increased. This is
probably due to the reason that Taniaphos-Cu is
3
.2 | Extraction of amino acid
enantiomers using different organic
solvents
1
0,27
conducive to combine with anionic amino acid.
This result suggested that the complexation between
−
The spatial configuration of Taniaphos-Cu might be
COO and Taniaphos-Cu plays an important role in
15
influenced
by
organic
solvent.
Thus,
the
enantioseparation. With the increase of the pH of water
phase, the α values increased at first and then achieved
an equilibrium at pH above 10.0. And α values slightly
decreased at pH of 12.0. This trend revealed that exces-
sively high pH would weaken the enantioselectivity of
enantioselectivities of Taniaphos-Cu in four different
organic solvents were evaluated, and the results were
shown in Table 2. Taniaphos-Cu showed good abilities to
enantioseparate amino acid enantiomers when Dic-
hloromethane, Chloroform, and 1,2-Dichloroethane were
used as organic solvent. The α values of Taniaphos-Cu in
10
Taniaphos-Cu complex. As reported in previous work,
high α values of chiral diphosphine ligands, such as
BINAP, DIOP, and SDP, were always obtained at pH
above 7.0. Which were lower than 10.0 reported in this
work. This difference suggested that OH may play an
important role between Taniaphos-Cu and amino acid
enantiomers. The ee values of D-amino acid enantiomers
in organic solvent increased at first and then decreased
with pH above 9.0. In chiral extraction, performance fac-
tor (pf) is often used to comprehensively evaluate the effi-
ciency of chiral extraction. High value of pf implied that
D-amino acid enantiomers are extracted into organic
1
,2-Dichloroethane are much bigger than that in other
solvents. And 1,2-Dichloroethane has lower volatility
compared with Dichloromethane and Chloroform. There-
fore, 1,2-Dichloroethane is the suitable organic solvent in
this work. When Chlorobenzene was used as organic sol-
vent, Taniaphos-Cu exhibited low enantioselectivities to
amino acid enantiomers. This result is very similar to
other chiral diphosphine ligands that were reported in
previous works. The precious works suggested that Chlo-
robenzene would disturb the π-π interaction of phenyl
15–17
28
groups between chiral extractants and substrates.
phase with high purity and high yield simultaneously.
Accordingly, π-π interaction between Taniaphos-Cu and
amino acid enantiomers might be an important acting
force in chiral extraction.
The curves of pf in Figure 2 revealed that high pf were
obtained at pH around 10.0. Thus, the following experi-
ments were carried out at pH 10.0.
TABLE 2 Enantioselectivities of Taniaphos-cu at different organic solvents
Dichloromethane Chloroform
1,2-Dichloroethane
Chlorobenzene
Amino acids
Phe
k
D
k
L
α
k
D
k
L
α
k
D
k
L
α
k
D
k
L
α
0.251
1.401
0.271
0.209
0.137
1.171
0.195
0.151
1.83
1.20
1.40
1.38
0.253
1.663
0.309
0.280
0.168
1.293
0.208
0.214
1.50
1.28
1.49
1.31
0.254
1.701
0.220
0.553
0.117
1.325
0.121
0.358
2.17
1.28
1.81
1.54
0.230
1.303
0.225
0.183
0.173
0.881
0.197
0.136
1.33
1.13
1.14
1.35
Hphe
Nphe
Cpheg

296
XIAO ET AL.
FIGURE 2 Enantioselectivities of Taniaphos-Cu at different pH
30
3.4 | Enantioselectivities of Taniaphos-
them. The curves of pf indicated that the optimal
Taniaphos-Cu concentrations for Phe, Hphe, Nphe, and
Cpheg were 2.0, 1.5, 1.5, and 2.0 mmol/L, respectively.
Cu at different concentration
Finding the optimal concentration range of Taniaphos-
Cu is important for improving extraction efficiency and
reducing extraction cost. The enantioselectivities of
Taniaphos-Cu at concentration of 0.25–3.0 mmol/L were
detected, and the results were depicted in Figure 3. With
increasing of Taniaphos-Cu concentration, there were
more extractants in organic phase that could combine
3.5 | Enantioselectivities OF Taniaphos-
Cu at different temperature
The enantioselectivities of Taniaphos-Cu at temperature
ꢀ
in the range of 5–25 C were detected. As shown in
with amino acid enantiomers. Thus, the values of k and
Figure 4, the values of kD and k for Nphe were both
D
L
kL were both deservedly increased with increasing
extractants concentration. The values of α were all
increased with increasing Taniaphos-Cu concentration
and then became stable with Taniaphos-Cu concentra-
tions around 1.5 mmol/L. Generally, there was a small
amount of racemic amino acid in organic phase that was
extracted by physical dissolution with non-stereo-
increased with increasing temperature. Generally, physi-
cal solubility of amino acid in organic phase increased
with increasing extraction temperature. Thus, k values
were always increased with increasing extraction temper-
ature. For the same reason, the value of α for Nphe was
negatively correlated with extraction temperature. This
31
phenomenon was similar to other diphosphine ligands
29
13,17
selectivity. This phenomenon would decrease the ee
values when Taniaphos-Cu concentration was low. Thus,
the curves of ee in Figure 3 were positively correlated
with Taniaphos-Cu concentration in the range of 0.25–
reported in previous studies.
However, k and k for
D L
other amino acid enantiomers were both decreased with
increasing temperature. And the values of α remained
stable with increasing temperature. This phenomenon
suggested that the structure of the substrate also has a sig-
nificant influence on the extraction. The nitro in amino
acid may play an important role in chiral extraction. The
curves in Figure 4 revealed that the values of ee for Nphe
slightly decreased with increasing temperature while the
1
.0 mmol/L. With the Taniaphos-Cu concentration fur-
ther increased, ee values were slightly decreased. This is
probably because that the competition between D- and L-
enantiomers decreased with there was too much
Taniaphos-Cu in organic phase that could combine with

XIAO ET AL.
297
FIGURE 3 Enantioselectivities of Taniaphos-Cu at different concentration
FIGURE 4 Enantioselectivities of Taniaphos-Cu at different temperature

298
XIAO ET AL.
values of ee for Phe, Hphe, and Cpheg slightly increased
with increasing temperature. The high values of pf were
obtained at temperature around 20 C. The above results
pf Nphe = −0:75743 + 0:16194A + 0:13312B
ð10Þ
2
2
+
0:013425AB−0:010019A −0:078175B ,
ꢀ
indicated that extraction temperature had no significant
effect on extraction. Therefore, the chiral extraction could
be carried out at room temperature. Compared with other
diphosphine ligands, Taniaphos-Cu had the advantage of
energy conservation in chiral extraction.
pf Cpheg = −0:79918 + 0:1571A + 0:08563B
2
2
+
0:00409AB−0:00828625A −0:029525B :
ð11Þ
In this work, the influences of pH and Taniaphos-Cu
concentration on pf and the statistical significance of the
mathematical models were investigated by analysis of
variance. The analyzed data for Phe, Hphe, Nphe, and
Cpheg were shown in Tables S2–S5, respectively. The
values of P for the fitted quadratic polynomial models
were all below 0.05, which indicated that the obtained
models fitted well with the experimental data in Table 3.
Also, the values of P for “lack of fit” were all greater than
0.05, indicating that the actual experimental data and
values predicted from models had no significant differ-
ences. P values also could be used to evaluate factors that
affected extraction significantly. For instance, P values
for A, A , and B were all below 0.05 indicating that pH,
quadratic levels of pH, and Taniaphos-Cu concentration
showed significant influence on pf in extraction of Phe.
After removing the nonsignificant influence parameters,
the simplified models for Phe, Hphe, Nphe, and Cpheg
were shown in Equations 12–15, respectively.
3
.6 | Optimization of the extraction
conditions
Response surface methodology design was always used to
design and evaluate the extraction conditions.
22,32
Based
on the results obtained in the above single factor experi-
ments, the ranges of pH and Taniaphos-Cu concentration
evaluated in optimization experiments were tabulated in
Table S1. The optimal conditions for extraction of amino
acid enantiomers by Taniaphos-Cu were investigated
with a central composite design (CCD). There were
1
3 runs carried out in CCD, and the results were tabu-
2
2
lated in Table 3. The extraction models were obtained by
a quadratic polynomial stepwise regression method. And
the mathematical models for Phe, Hphe, Nphe, and
Cpheg were shown in Equations 8–11, respectively.
pf Phe = −1:24712 + 0:24515A + 0:080011B
ð8Þ
2
2
+
0:004605AB−0:012433A −0:031422B ,
2
2
pf Phe = −1:24712 + 0:24515A – 0:012433A – 0:031422B ,
ð12Þ
pf Hphe = −1:48246 + 0:2746A + 0:19023B
ð9Þ
2
pf Hphe = −1:48246 + 0:2746A + 0:19023B−0:011868A ,
2
2
−
0:01671AB−0:011868A + 0:0002785B ,
ð13Þ
TABLE 3 The pf values obtained in
Run
X
1
X
2
pf (Phe)
0.08461
0.06023
0.08877
0.07055
0.07555
0.08826
0.08647
0.07646
0.08962
0.06055
0.07313
0.06602
0.05557
pf (Hphe)
0.1173
0.07023
0.1038
0.1171
0.1254
0.1147
0.1146
0.09543
0.1098
0.1196
0.1009
0.1095
0.06389
pf (Nphe)
0.09106
pf (Cpheg)
0.07821
0.06298
0.07739
0.06993
0.06482
0.07662
0.07701
0.05822
0.08167
0.06747
0.06578
0.05215
0.05875
CCD experiments
1
2
3
4
5
6
7
8
9
0
0
−1
−1
0.05762
0.09504
0.07365
0.07773
0.09609
0.09479
0.04121
0.09063
0.06010
0.07842
0.04840
0.07454
0
0
0
1.41
1
1
0
0
0
0
0
−1.41
0
0
10
11
12
13
−1
1.41
1
1
0
−1
0
−1.41

XIAO ET AL.
299
pf Nphe = −0:75743 + 0:13312B + 0:013425AB
ð14Þ
Taniaphos-Cu. The highest pf was obtained at pH around
10.0 and Taniaphos-Cu concentration around 2.2 mmol/L.
2
2
−
0:010019A – 0:078175B ,
The optimal extraction conditions for Phe, Hphe,
Nphe, and Cpheg could be predicted by mathematical
models in Equations 12–15. The optimal extraction
conditions and the predicted highest pf were shown in
Table S6. For instance, the optimal extraction condi-
tion for Phe is at pH of 10.20, and Taniaphos-Cu con-
centration of 2.0 mmol/L with the predicted pf is
0.08822. At these optimal extraction conditions, the
experimental pf values were also detected. The relative
errors between predicted and experimental pf for Phe,
Hphe, Nphe, and Cpheg were 0.79%, 1.85%, 1.23%, and
1.78%, which indicated that the models are efficient in
the prediction of optimal extraction conditions and
pf values.
2
2
pf Cpheg = −0:79918 + 0:08563B−0:00828625A – 0:029525B :
ð15Þ
The three-dimensional response surface graphs of pf
at different pH and Taniaphos-Cu concentration were
shown in Figure 5. For Phe, the curve of pf is similar to a
parabola with increasing pH or Taniaphos-Cu. The
highest pf was obtained at pH around 10.0 and
Taniaphos-Cu concentration around 2.0 mmol/L. For
Hphe, pf values sharply increased with increasing pH
and then slightly decreased with pH above 10.5. When
pH was below 10.5, pf values increased with increasing
Taniaphos-Cu concentration. However, pf values
decreased with increasing Taniaphos-Cu concentration at
pH above 10.5. For Nphe, pf values slightly increased
with increasing pH and then significantly decreased with
pH above 8.5. The pf values significantly increased
with Taniaphos-Cu concentration in the range of 0.8–
3.7 | Recognition mechanism between
Taniaphos-Cu and amino acid enantiomers
Analysis of the recognition mechanism between
Taniaphos-Cu and amino acid enantiomers is important
for design and synthesizing new chiral extractants in
future work. The results in Table 2 showed that
1
.8 mmol/L and then slightly decreased with Taniaphos-
Cu concentration further increased. For Cpheg, the curve
of pf is similar to a parabola with increasing pH or
FIGURE 5 The three-dimensional response surface graphs of pf at different pH and Taniaphos-Cu concentration

300
XIAO ET AL.
FIGURE 6 The possible recognition
mechanism between Taniaphos-Cu and
amino acid enantiomers
Taniaphos-Cu exhibited low enantioselectivities to amino
acid enantiomers in the solvent of Chlorobenzene. This
phenomenon suggested that Chlorobenzene would dis-
turb the π-π interaction of phenyl groups between chiral
enantiomers. Taniaphos-Cu is more conducive to com-
bine with D-Phe, D-Hphe, D-Nphe, and D-Cpheg with
the highest α of 3.13, 2.10, 2.32, and 2.14, respectively.
The influences of pH, Taniaphos-Cu concentration, and
extraction temperature on extraction were comprehen-
sively evaluated. The results showed that Taniaphos-Cu
is conducive to combine with the anionic amino acid.
And the enantioselectivity of Taniaphos-Cu is insensitive
to extraction temperature. After optimization by CCD,
the highest pf for Phe, Hphe, Nphe, and Cpheg were
0.08892, 0.1250, 0.09621, and 0.08021, respectively. The
coordination interaction between Taniaphos-Cu and
26
extractants and substrates. Accordingly, π-π interaction
between Taniaphos-Cu and amino acid enantiomers
might be an important acting force in chiral extraction.
The results in Figure 2 revealed that Taniaphos-Cu is
conducive to combine with the anionic amino acid. Thus,
−
the complexation between COO and Taniaphos-Cu is
12,15
another important acting force in chiral extraction.
After chiral extraction, the organic solution was further
analyzed by mass spectrometry to verify the complexes of
Taniaphos-Cu enantiomers. The mass spectrometries of
organic solution extracted with D-Phe and L-Phe were
−
COO , π-π interaction between Taniaphos-Cu and
amino acid enantiomers are important acting forces in
chiral extraction. The steric-hindrance between NH2
and OH lead to Taniaphos-Cu-D-Phe is more stable
than Taniaphos-Cu-L-Phe.
shown in Figures S1 and S2. The molecular ion peaks at
+
9
34.2 [M + 1] indicated that molecular weights of
Taniaphos-Cu-D-Phe and Taniaphos-Cu-L-Phe were both
33.2. Based on the above discussion, the possible chemi-
9
ACKNOWLEDGMENT
cal structures of Taniaphos-Cu-D-Phe and Taniaphos-Cu-
L-Phe were proposed in Figure 6. The molecular formu-
las of Taniaphos-Cu-D-Phe and Taniaphos-Cu-L-Phe
were C H CuFeN O P with calculated molecular mass
of 933.2. In chiral extraction, amino acid enantiomers
and OH were extracted into organic phase and
combined with Taniaphos-Cu to form a tetrahedral com-
plex. Hydroxide ion was directly involved in extraction
process. It explained why the optimal pH for Taniaphos-
Cu is much higher than other chiral diphosphine
ligands reported in previous work (Figure 3). The steric-
This work was financially supported by National Natural
Science Foundation of China (Grant No. 51703060).
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are
available from the corresponding author upon reasonable
request.
52
52
2 3 2
ORCID
Xiong Liu https://orcid.org/0000-0001-9916-116X
hindrance between NH and OH would decrease the
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How to cite this article: Xiao W, Chen S, Liu X,
Ma Y. Investigation of Taniaphos as a chiral
selector in chiral extraction of amino acid
enantiomers. Chirality. 2021;33:292–302. https://
doi.org/10.1002/chir.23309
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.