Chromatographic approach to study the configurational stability of Ni(II) complexes of amino-acid Schiff bases possessing stereogenic nitrogen

Article abstract of DOI:10.1002/chir.23059

Herein, we disclose the design of a model Ni(II) complex of glycine Schiff base possessing single-nitrogen stereogenic center, which was successfully used for high-performance liquid chromatography (HPLC)-assisted assessment of its configurational stability. The major finding is that the configurational stability of the Ni(II)-coordinated nitrogen is profoundly dependent on the reaction conditions used, in particular the solvent, and can range from inconsequential (t_? less than 5?min) to virtually completely stable (t_? 90?y). The discovery reported in this study most likely to be of certain theoretical and synthetic value.

Full text of DOI:10.1002/chir.23059

Received: 15 November 2018
DOI: 10.1002/chir.23059
Revised: 3 January 2019
Accepted: 4 January 2019
R E G U L A R A R T I C L E
Chromatographic approach to study the configurational
stability of Ni(II) complexes of amino‐acid Schiff bases
possessing stereogenic nitrogen
Jianlin Han1
| Marion Jean2 | Christian Roussel2 | Hiroki Moriwaki3 |
Vadim A. Soloshonok4,5
1 College of Chemical Engineering,
Nanjing Forestry University, Nanjing,
China
2 Aix‐Marseille University, CNRS,
Centrale Marseille, iSm2, Marseille,
France
Abstract
Herein, we disclose the design of a model Ni(II) complex of glycine Schiff base
possessing single‐nitrogen stereogenic center, which was successfully used for
high‐performance liquid chromatography (HPLC)‐assisted assessment of its con-
figurational stability. The major finding is that the configurational stability of the
Ni(II)‐coordinated nitrogen is profoundly dependent on the reaction conditions
3 Hamari Chemicals Ltd., Osaka, Japan
4 Department of Organic Chemistry I,
Faculty of Chemistry, University of the
Basque Country UPV/EHU, San
Sebastián, Spain
5 IKERBASQUE, Basque Foundation for
Science, Bilbao, Spain
used, in particular the solvent, and can range from inconsequential (t less than
½
5 min) to virtually completely stable (t 90 y). The discovery reported in this
½
study most likely to be of certain theoretical and synthetic value.
KEYWORDS
amino acids, axial chirality, chiral HPLC, kinetic of racemization, rotational energy barriers
Correspondence
Vadim A. Soloshonok, Department of
Organic Chemistry I, Faculty of
Chemistry, University of the Basque
Country UPV/EHU, Paseo Manuel
Lardizábal 3, 20018 San Sebastián, Spain.
Email: vadym.soloshonok@ehu.es
Funding information
Changzhou Jin‐Feng‐Huang program;
Basque Foundation for Science;
IKERBASQUE; National Natural Science
Foundation of China, Grant/Award
Number: 21761132021
1 | INTRODUCTION
χ‐space3 is a well‐established paradigm in the design of
modern pharmaceuticals.1,4,5 Consequently, the current
Amino acids (AAs) are among a few essential compounds
intricately involved in some basic aspects of the phenom-
enon of life. They played a momentous role in the devel-
opment of organic, bio‐organic, medicinal, and
pharmaceutical chemistry shaping up the modern
healthcare industry and life sciences.1 Nowadays, the
use of tailor‐made2 AAs in the design of peptides/
peptidomimetics with restricted number of conforma-
tions and precise positioning of the side chains in the
interest in chemistry of tailor‐made AAs6 and their ana-
logs, in particular fluorine‐containing,7 sulfonic,8 and
phosphonic9 derivatives, is at an all‐time high, exploring
new structural ideas, functions, and bio‐properties. Con-
sistent with our long‐standing interest in asymmetric syn-
thesis of tailor‐made AAs10 and their nonlinear
chiroptical properties, such as self‐disproportionation of
enantiomers,11 we were actively contributing to the
development of the Ni(II) complex chemistry of AA Schiff
Chirality. 2019;1–8.
wileyonlinelibrary.com/journal/chir
© 2019 Wiley Periodicals, Inc.
1

2
HAN ET AL.
bases as a generalized methodology for preparation of
various types of tailor‐made AAs (Scheme 1).4,6,12
As shown in Scheme 1, generally represented ligand
(S)‐ or (R)‐1, bearing stereochemical information on one
of their structural elements, can be transformed into the
corresponding glycine derivative or used directly for com-
plexation with AAs. The latter case can be used for the
deracemization, dynamic kinetic resolution, or (S) to (R)
interconversion of unprotected α‐ and β‐AAs.13,14 On
the other hand, the square‐planar Gly‐Ni(II) complex 2
serves as a useful chiral nucleophilic glycine equivalent
to be transformed into the intermediates 3 via homologa-
tion with variety of electrophilic reagents. Typically used
reaction types include alkyl halide alkylations,15
Michael,16 aldol, and Mannich17 addition reactions. Com-
pounds 3 can be disassembled under operationally conve-
nient conditions to afford AAs of general types 4 to 10
along with recovery of chiral ligands 1. Using the modu-
lar approach to the design of chiral ligands,18 recently,
we have developed novel types of ligands and the corre-
sponding Gly‐Ni(II) complexes exploring different forms
of chirality (Figure 1).
FIGURE
1
Structural types of chiral ligands and the
corresponding Gly‐Ni(II) complexes 11 to 15 of glycine Schiff base
from chiral amines, as a source of stereochemical infor-
mation.22 In particular, application of complexes 14
allowed us to perform the synthesis of some α‐AAs using
the esoteric case of a second‐order asymmetric transfor-
mation control.23 The rare properties of compounds 14
were found to result from a combination of configura-
tionally stable stereogenic carbon with configurationally
unstable stereogenic nitrogen of the amine residue. To
further the synthetic applications of this type of chiral
ligands and the corresponding Ni(II) complexes, we real-
ized that it might be highly desirable to quantify the con-
figurational stability of the stereogenic nitrogen in
compounds 14. In this work, we describe synthesis of spe-
cially designed complex 15, chiral HPLC‐assisted separa-
tion of the enantiomers,24 and their racemization rates
as a measure of configurational stability of the stereo-
genic nitrogen in 15.
For example, complex 1119 possesses a traditional cen-
tral chirality located on the α‐carbon of the proline resi-
due. On the other hand, the stereochemical information
in complex 1220 is provided by the axial chirality of di‐
benzo‐azepin moiety. Curious case of double asymmetric
induction is presented by complex 13 featuring the cen-
tral along with the axial chirality, resulting from a
restricted rotation of the o‐chloro‐phenyl moiety.21 More
recently, we developed compounds of type 14, derived
2 | MATERIALS AND METHODS
2.1 | General information
All commercial reagents were used without additional
purification unless otherwise specified. All experiments
were monitored by thin‐layer chromatography (TLC)
using ultraviolet (UV) light as visualizing agent. 1H
nuclear magnetic resonance (NMR) (400 MHz), 13C
NMR (101 MHz), and 19F NMR (376 MHz) were mea-
sured on Bruker AVANCE III‐400 spectrometer. Melting
points are uncorrected. Infrared spectra were obtained
on Bruker Vector 22 in KBr pellets. High resolution mass
spectrum (HRMS) was recorded on a LTQ‐Orbitrap XL
(Thermo Fisher, USA).
SCHEME 1 General approach for preparation of tailor‐made
amino acids (AAs) of types 4 to 10 via chiral ligands 1 and
homologation of nucleophilic glycine equivalents 2

HAN ET AL.
3
propylamine. As was shown previously,25 the application
of Hünig's base (DIPEA) is essential for preparation of
mono‐alkylated product 18 in good chemical yield. Synthe-
sis of the target racemic Ni(II) complex (R/S)‐15 was per-
formed in methanol starting from ligand 18, glycine,
Ni(OAc)2, as a source of Ni(II) ions, and Na2CO3 as a base.
Complex (R/S)‐15 was carefully purified by column chro-
matography on silica gel and fully characterized.
It should be emphasized that separation of enantio-
mers containing stereogenic N―H nitrogen coordinated
to a metal, like the type presented by complex 15, has
never been described in the literature. Accordingly, while
being novel and scientifically exciting, possibility of the
separation, detection, and study of the enantiomers of
compound 15 was far from certain. Thus, drawing inspi-
ration from our recent study on the chromatographic sep-
aration of enantiomers of axially chiral Ni(II) complexes
of glycine and other amino acids,26 we proceeded with a
comprehensive search for proper chromatographic reso-
lution conditions. Taking advantage of available to us
(Marseille group), entirely automated equipment for
screening chiral separation conditions (stationary phases,
solvents, temperature, and chiroptical detection), we
eventually identified reasonably good separation condi-
tions presented in Figure 2.
As one can see from Figure 2, the enantiomers 15
were quite successfully separated over several chiral amy-
lose carbamates stationary phases, such as, Chiralpak IA
and ID. These results were a crucial breakthrough in
our work as they provided the physical evidence that
the enantiomers are sufficiently stable to be separated
and collected for off‐line studies. Nevertheless, working
with the ethanolic solutions of separated enantiomers
15, we observed their tendency to partial racemization
at ambient temperatures. Accordingly, we optimized the
working procedure in a way that immediately after the
preparative chiral HPLC separation, using ethanol as a
mobile phase, the separated fractions of enantiomers 15
were kept and then evaporated at temperatures lower
than 5°C. This procedure allowed us to obtain enantio-
mers 15 with excellent excess of substrate (ees).
2.2 | General synthetic procedures and
experimental methods synthesis of 18
To a slurry of 17 (1 equiv) and potassium carbonate (1.2
equiv) in acetonitrile was added the corresponding amine
(1.1 equiv). The reaction was allowed to proceed for
2 hours at 60°C to 70°C (monitored by TLC) before the
reaction mixture was concentrated under vacuum. Water
was added to the viscous liquid, followed by extraction
with dichloromethane. The organic portions were com-
bined, dried with magnesium sulfate. The solvent was
evaporated to give the crude product 18, which was puri-
fied by flash chromatography (For details, see Supporting
Information).
2.3 | Synthesis of 15
An oven‐dried reaction vial containing 18 (0.2 mmol), gly-
cine (5 equiv), nickel nitrate hexahydrate (2 equiv), and
K2CO3 was evacuated and purged with argon three times.
Then, MeOH (4 mL) as solution was added via syringe at
ambient temperature, respectively. Then, the reaction
mixture was stirred for 8 hours at ambient temperature,
and then, the reaction was quenched with H2O (5 mL).
The organic layer was removed, and the aqueous layer
was extracted with DCM (2 × 5 mL). The combined
organic layers were washed with H2O (2 × 10 mL) and
brine solution (1 × 10 mL) and dried over anhydrous
Na2SO4. The solvent was evaporated to give the crude
product 15, which was purified by flash chromatography
(For details, see Supporting Information).
3 | RESULTS AND DISCUSSION
Commercially available o‐amino‐benzophenone 16
(Scheme 2) was selectively mono‐acylated with
bromoacetyl bromide in a solution of acetonitrile, to afford
amide 17. Compound 17 was isolated and reacted with iso‐
Having developed a reliable approach for separation of
enantiomers 15, we were in position to perform a compre-
hensive study of their configurational stability. Following
the successful methodology of our previous chromato-
graphic study of axially chiral Ni(II) complexes,26 the race-
mization of enantiomer 15 was followed at a particular
temperature by monitoring the enantiomeric ratios as a
function of time. The enantiomerization (racemization)
rate was deduced from the slope of the first‐order kinetic
line. The results obtained are presented in Table 1.
As mentioned above, enantiomers 15 were found to be
relatively stable in ethanolic solutions allowing their
SCHEME 2 Synthesis of ligand 18 and racemic glycine Schiff
base Ni(II) complex 15 containing stereogenic nitrogen

4
HAN ET AL.
FIGURE 2 Room temperature separation of enantiomers of Ni(II) complex 15 on Chiralpak IA and Chiralpak ID columns
TABLE 1 Enantiomerization barriers and half‐live time for enantiomer 15 in different solvents
Kinetics of Enantiomerization
Entry
Solvent
k (s−1
)
ΔG≠ (kJ/mol)
T (°C)
t
Dielectric Constant
t
at 25°Ca
½
½ (at T)
1
2
H2O
nd
nd
<90
20
20
<5 min
<5 min
2 h
78.4
37.5
32.6
25.3
20.2
<5 min
<5 min
1 h 20 min
7 h
MeCN
MeOH
EtOH
<90
3
4.85 10−5
9.05 10−6
1.72 10−5
4.77 10−5
5.84 10−6
4.93 10−7
1.39 10−6
1.72 10−5
96.7
22
4
100.8
99.2
22
10.6 h
5.6 h
2 h
5
i‐PrOH
MTBE
THF
22
4 h
6
107.8
117.4
122.9
125.5
129.6
55
5 d
7
66
16.5 h
8 d
7.4
4.81
6
239 d
6 y
8
CHCl3
Ethyl acetate
Toluene
62
9
77
69 h
17 y
10
110
10 h
2.38
90 y
aEstimated with the hypothesis that the enantiomerization barrier is constant with temperature.
separation and isolation. Therefore, we were quite surprised
to discover that in aqueous solution, the enantiomers 15 are
utterly configurationally unstable with the racemization rate
being so fast that it cannot be even accurately measured
using the present approach. All we could do was the estima-
tion that the enantiomerization proceeds with ΔG≠ less than
in solutions of acetonitrile (entry 2), indicating some general-
ity in the configurational instability of enantiomers 15 in
highly polar solvents. In sharp contrast to water (entry 1)
and acetonitrile (entry 2), the experiments performed in alco-
holic solutions (entries 3‐5) were very successful allowing for
a complete description of the enantiomerization process.
Thus, in the methanol, we determined the following data:
kenantiomerization = 4.85 10−5 s−1 (22°C, methanol) with the
90 kJ/mol with t racemization less than 5 minutes (entry 1).
½
The same results were observed conducting the experiments

HAN ET AL.
5
ΔG≠ equal 96.7 kJ/mol, indicating that t racemization for
should be noted that we failed to find in the literature
any analogs or precedents to this trend observed for com-
pounds with nitrogen stereogenic center. Therefore, we
believe that these results obviously present a novel phe-
nomenon of greater scientific and practical importance.
Some rationalization of the results obtained can be
outlined using the chain of reactions presented in
Scheme 3.
½
enantiomers 15 is only 1 hour and 20 minutes (entry 3).
The experiments performed in ethanol revealed noticeably
greater configurational stability of 15 as compared with that
of methanol. Thus, the data obtained (entry 4)
kenantiomerization = 9.05 10−6 s−1 (22°C, ethanol) with the
ΔG≠ = 100.8 kJ/mol indicated that t racemization for enan-
½
tiomers 15 is 7 hours. Similar data were obtained in the
experiments conducted in isopropanolic solutions (entry 5).
In this case, the kenantiomerization = 1.72 10−5 s−1 (22°C,
The broad literature data on the ligand exchange mech-
anisms at metal centers27 adopt a typical associative
nucleophile‐coordination‐N‐discoordination mechanism28
via formation of N―Ni‐noncoordinated intermediate 16.
This mechanism would perfectly support the results
obtained in such solvents as water (entry 1), acetonitrile
(entry 2), and alcohols (entries 3‐5). To some extent, the
ethers (entries 6 and 7) and ethyl acetate (entry 9) can be
considered as possessing nucleophilic groups with an abil-
ity to coordinate to the Ni(II). On the other hand, chloro-
form (entry 8) and toluene (entry 10) would hardly act as
nucleophiles coordinating to the metal. Thus, the question
of configurational stability of stereogenic nitrogen has to be
always asked in context of the reaction conditions, in par-
ticular a solvent or presence of any other nucleophiles.
For example, stereogenic nitrogen center of compound 15
in water is very configurationally unstable and can be
somehow disregarded as an element of chirality in aqueous
medium. In sharp contrast, the configurational stability of
nitrogen in 15 in nonnucleophilic medium is exceptionally
high and can be used for synthetic purposes as a stable ele-
ment of stereochemical information. Nevertheless, the data
obtained in this work show more complex relationships
between the configurational stability and the solvent nucle-
ophilicity. For instance, in the alcohols series (entries 3‐5),
the dependence of the observed ΔG≠ and dielectric con-
stant of the solvents are not linear, suggesting some role
of steric effects or other factors. Similar discrepancy can
be seen in the ethers series (entries 6 and 7) where the dif-
ference in the observed ΔG≠ cannot be accounted for sim-
ply by nucleophilic considerations. Also, ethyl acetate
(entry 9), possessing somehow nucleophilic oxygens, was
found to perform more likely total nonnucleophilic sol-
vent. Evidently, further design of model compounds of type
isopropanol) with the ΔG≠ = 99.2 kJ/mol and t racemiza-
½
tion for enantiomers 15 making 4 hours.
Careful analysis of these data (entries 1‐5) allowed us to
notice that configurational stability of enantiomers 15 can
be roughly correlated with the polarity of the solvent used,
in particular its dielectric constant value. This prompted us
to continue our study using other types of organic solvents.
Thus, next set of experiments was conducted in ether‐type
solvents. Quite surprisingly, in MTBE, the configurational
stability of enantiomers 15 was found to be noticeably
increased making it necessary to elevate the experimental
temperature from 22°C to 55°C (entry 6). In particular,
the kenantiomerization was detected to be 4.77 10−5 s−1 (55°C,
MTBE) with the ΔG≠ = 107.8 kJ/mol, which corresponds
to t racemization for enantiomers 15 of 5 days. In another
½
ether‐type solvent, THF (entry 7), the configurational sta-
bility of enantiomers 15 was found to be markedly greater.
As one can see from entry 7, the experiments were con-
ducted at 66°C, recording kenantiomerization = 5.84 10−6 s−1
(66°C, THF) affording the ΔG≠ = 117.4 kJ/mol making
the t racemization for enantiomers 15 equivalent of
½
239 days. Inspired by these unexpected results, we selected
yet another three common organic solvents presented in
entries 8 to 10. Thus, in chloroform (entry 8), the
experiments were conducted at nearly the solvent
boiling point and gave the following values:
kenantiomerization = 4.93 10−7 s−1 (62°C, chloroform),
ΔG≠ = 122.9 kJ/mol, t racemization for enantiomers 15
½
equaling astounding 6 years. In ethyl acetate, possessing a
higher boiling point, we conducted experiments at 77°C
allowing to record the kenantiomerization = 1.39 10−6 s−1
(77°C, ethyl acetate), ΔG≠ = 125.5 kJ/mol leading to t
½
racemization for enantiomers 15 of stunning 17 years.
Finally, the experiment conducted in toluene, again at
nearly the solvent boiling point, revealed extraordinary
level of enantiomers 15 configurational stability,
kenantiomerization
=
1.72 10−5 s−1 (110°C, toluene),
ΔG≠ = 129.6 kJ/mol. The calculated t racemization for
½
enantiomers 15 in toluene equalled of 90 years.
The observed range, from ΔG≠ = <90 to 129.6 kJ/mol,
with t less than 5 minutes to 90 years, of the configura-
½
tional stability of the stereogenic nitrogen in Ni(II) com-
plexes 15 was, to say the least, totally unexpected. It
SCHEME 3 Proposed nucleophile‐assisted mechanism for the
racemization of Ni(II) complex 15

6
HAN ET AL.
highly sterically constrained (2S,3S)‐3‐methyl‐3‐trifluoromethyl‐
and (2S,3S,4R)‐3‐trifluoromethyl‐4‐methylpyroglutamic acids.
Tetrahedron 1999:55:12045–12058, 41.
15 with controllable steric and electronic factors is highly
desirable for more detailed study of this phenomenon. Fur-
thermore, as suggested by one of the referees, a relation-
ship could be considered between ΔG≠ and solvent
coordination capacity29 and pKa.
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4 | CONCLUSION
We demonstrate that the properly designed Ni(II) com-
plex of glycine Schiff base possessing single‐nitrogen ste-
reogenic center can be successfully used to assess its
configurational stability via HPLC‐assisted kinetic race-
mization experiments. We show that the configurational
stability of the Ni(II)‐coordinated nitrogen is a function
of solvent, more generally reaction conditions, and can
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range from insignificant (t less than 5 min) to quite sta-
½
ble (t 90 y). The data reported in this study allow for
½
rational prediction of the stereochemical properties of
the stereogenic nitrogen coordinated to Ni(II) and would
be quite helpful in the design of new chiral ligands as
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gested by one of the referees, further exploration of this
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ACKNOWLEDGMENTS
Dr Nicolas Vanthuyne, the Chiral Chromatography Cen-
ter of Aix‐Marseille University, is warmly thanked for
performing chiral chromatography experiments. We
gratefully acknowledge the financial support from the
National Natural Science Foundation of China (no.
21761132021), the IKERBASQUE, Basque Foundation
for Science, and Changzhou Jin‐Feng‐Huang program.
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ORCID
Jianlin Han https://orcid.org/0000-0002-3817-0764
Vadim A. Soloshonok
4526
https://orcid.org/0000-0003-0681-
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
How to cite this article: Han J, Jean M, Roussel
C, Moriwaki H, Soloshonok VA. Chromatographic
approach to study the configurational stability of
Ni(II) complexes of amino‐acid Schiff bases
possessing stereogenic nitrogen. Chirality.
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2019;1–8. https://doi.org/10.1002/chir.23059