Effect of substituents on the configurational stability of the stereogenic nitrogen in metal(II) complexes of α-amino acid Schiff bases

Article abstract of DOI:10.1002/chir.23066

Herein, we report a general method for quantitative measurement of the configurational stability of the stereogenic nitrogen coordinated to M (II) in the corresponding square planar complexes. This stereochemical approach is quite sensitive to steric and electronic effects of the substituents and shown to work well for Ni(II), Pd(II), and Cu(II) complexes. Structural simplicity of the compounds used, coupled with high sensitivity and reliability of experimental procedures, bodes well for application of this approach in evaluation of chemical stability and stereochemical properties of newly designed chiral ligands for general asymmetric synthesis of tailor-made amino acids.

Full text of DOI:10.1002/chir.23066

Received: 31 January 2019
DOI: 10.1002/chir.23066
Revised: 27 February 2019
Accepted: 1 March 2019
R E G U L A R A R T I C L E
Effect of substituents on the configurational stability of the
stereogenic nitrogen in metal(II) complexes of α‐amino acid
Schiff bases
Haibo Mei1 | Marion Jean2 | Muriel Albalat2 | Nicolas Vanthuyne2 | Christian Roussel2 |
Hiroki Moriwaki3 | Zizhen Yin1 | Jianlin Han1
| Vadim A. Soloshonok4,5
1 College of Chemical Engineering,
Abstract
Nanjing Forestry University, Nanjing,
Herein, we report a general method for quantitative measurement of the con-
figurational stability of the stereogenic nitrogen coordinated to M (II) in the
corresponding square planar complexes. This stereochemical approach is quite
sensitive to steric and electronic effects of the substituents and shown to work
well for Ni(II), Pd(II), and Cu(II) complexes. Structural simplicity of the
compounds used, coupled with high sensitivity and reliability of experimental
procedures, bodes well for application of this approach in evaluation of chem-
ical stability and stereochemical properties of newly designed chiral ligands for
general asymmetric synthesis of tailor‐made amino acids.
China
2 iSm2, Aix Marseille Université, Marseille,
France
3 Hamari Chemicals Ltd., Osaka, Japan
4 Department of Organic Chemistry I,
Faculty of Chemistry, University of the
Basque Country, San Sebastián, Spain
5 IKERBASQUE, Basque Foundation for
Science, Bilbao, Spain
Correspondence
Christian Roussel, iSm2, Aix Marseille
Université, Marseille, France.
Email: christian.roussel@univ‐amu.fr
KEYWORDS
amino acids, chiral HPLC, kinetic of racemization, metal(II) complexes, Schiff bases, stereogenic
nitrogen
Jianlin Han, College of Chemical
Engineering, Nanjing Forestry University,
Nanjing, 210037, China.
Email: hanjl@njfu.edu.cn
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
National Natural Science Foundation of
China, Grant/Award Number:
21761132021
1 | INTRODUCTION
introduced drugs contained at least one tailor‐made AA
residue.2 Consequently, the development of synthetic
Tailor‐made amino acids (AAs),1 are essential structural
features of numerous modern pharmaceuticals.2 Applica-
tion of AA residues in drug design allows for fairly accu-
rate 3‐D positioning of pharmacophoric moieties and
mimicking the targeted biogenic peptide−receptor inter-
actions.3 Thus, over the past decade, about 20% of newly
methodology for preparation of tailor‐made AAs is cur-
rently in very high demand.4 Following our long‐standing
interest in synthesis of sterically constrained5 and
fluorine‐containing AAs,6 we were actively contributing
to the general asymmetric synthesis of α‐AAs via Ni(II)
complexes of AA Schiff bases (Scheme 1).7
Chirality. 2019;1–9.
wileyonlinelibrary.com/journal/chir
© 2019 Wiley Periodicals, Inc.
1

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MEI ET AL.
nitrogen as a function of stereo/electronic properties of
the N‐ligand substituents as well as the nature coordinat-
ing metal M(II).
2 | MATERIALS AND METHODS
2.1 | General information
All commercial reagents were used without additional
purification unless otherwise specified. Solvents were
purified and dried according to standard methods prior
to use. All experiments were monitored by thin layer
chromatography (TLC) using ultraviolet (UV) light as
visualizing agent. Column chromatography was per-
1
formed using silica gel 60 (300‐400 mesh). H NMR (400
SCHEME 1 General asymmetric synthesis of α‐amino acids via
homologation of Gly Schiff base Ni(II) complexes 2, bearing
stereochemical information on structural moieties A and/or B
MHz) and 13C NMR (101 MHz) were measured on Bruker
AVANCE III‐400 spectrometer. Melting points are uncor-
rected. Values of optical rotation were measured on
Rudolph Automatic Polarimeter A21101 at the wave-
length of the sodium D‐line (589 nm). Infrared spectra
were obtained on Bruker Vector 22 in KBr pellets. HRMS
were recorded on a LTQ‐Orbitrap XL (Thermofisher,
Waltham, Massachusetts).
As demonstrated by our and other research groups,
homologation of chiral nucleophilic glycine equivalents
2 via, for example, alkylations, Michael, aldol, and
Mannich addition reactions, offers a general approach
to various structurally and functionally varied tailor‐
made AAs.8 Disassembly of homologation products 3 is
conducted under simple acidic conditions allowing isola-
tion of the target AAs 4 along with a complete recovery of
chiral ligands 1, as well as the Ni(II), underscoring the
practicality of this methodology. Using modular
approach9 for the design of ligands 1, numerous glycine
complexes 2 were prepared with the aim to improve the
synthetic value and scalability of this methodology.8
However, the rational design of better performing ligands
and the corresponding Ni(II) complexes of AA Schiff
bases is still hindered by incomplete understanding
of the effects of ligands 1 structure on the stability and
reactivity of target complexes 2. For example, as concep-
tually shown in Scheme 1, structural areas A, B as well
as substituents X, can bear aliphatic, aromatic, electron‐
withdrawing/donating moieties imparting the strength
of the nitrogen‐nickel coordination bond, chelate rings
and, therefore, the overall stability of the Ni(II)
complexes of this type. Accordingly, we envisioned that
the development of viable approaches for quantitative
measurement of nitrogen‐metal bond stability would
have a profound impact on
2.2 | General procedures for the reaction
between o‐amino‐benzophenones 7 and
bromoacetyl bromide
A solution of bromoacetyl bromide (46 mmol) in acetoni-
trile (2 mL/1 g of bromoacetyl bromide) was slowly added
to a slurry of 2‐aminobenzophenone (20.4 mmol) and
potassium carbonate (102.2 mmol) in acetonitrile. The
reaction was stirred at ambient temperature for 1 hour,
and upon completion (monitored by TLC), the acetoni-
trile was evaporated under vacuum. Fifty milliliter of
water was then added to the crude mixture and extracted
with dichloromethane 50 mL for three times. The organic
portions were combined and dried over anhydrous
Na2SO4. The solvent was evaporated to give the crude
product 8, which was purified by flash chromatography.
2.3 | General procedures for preparation
of 9
the advancement of structural design of Ni(II) com-
plexes 2 and their synthetic applications. Here, we report
an innovative approach for experimental probing of the
nitrogen‐metal bond coordination energies using model
compounds derived from metal(II) complexes of glycine
Schiff base. The key feature of this work is the direct
probing the configurational stability of stereogenic
To a slurry of 8 (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

MEI ET AL.
3
combined and dried with magnesium sulfate. The solvent
was evaporated to give the crude product 9, which was
purified by flash chromatography.
washed with H2O (2 × 10 mL) and brine (1 × 10 mL)
and dried over anhydrous Na2SO4. The solvent was evap-
orated to give the crude product 10j, which was purified
by flash chromatography.
2.4 | General procedures for preparation
of Ni(II) complex (10a‐h)
2.7 | Chiral chromatography
Analytical columns (250 x 4.6 mm, 5 microns), Chiralpak
IA, IB, IC, ID, and (S,S)‐Ulmo were thermostated and
used to optimize the enantiomer separations, to deter-
mine ee and for dynamic chiral HPLC. Preparative col-
umns (250 x 10 mm, 5 microns) were used to collect the
enantiomers. The resulting solutions were kept in an ice
bath during the separative process and below 10°C during
the evaporation.
An oven‐dried reaction vial containing 9 (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. 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 (1 × 10 mL) and
dried over anhydrous Na2SO4. The solvent was evapo-
rated to give the crude product 10, which was purified
by flash chromatography.
3 | RESULTS AND DISCUSSION
Recently, we demonstrated that Ni(II)‐complex
5
(Scheme 2) can be successfully used to assess its configu-
rational stability of the stereogenic nitrogen via HPLC
assisted kinetic racemization experiments.10a Our prelim-
inary studies10 served as a convincing demonstration of
the viability of the chosen HPLC‐based approach for
working with Ni(II) complexes of AA Schiff bases. In
particular, for Ni(II) complex 5, we reported that the con-
figurational stability of the Ni(II)‐coordinated nitrogen
significantly depends on the solvent used for the experi-
ments. Thus, in strongly coordinating solvents,11 such as
water, acetonitrile, or alcohols, the configurational stabil-
ity of the stereogenic nitrogen is rather low with the t½ of
racemization ranging from greater than 5 minutes to
several hours. In sharp contrast, in solvents such as chlo-
roform, ethyl acetate, or toluene, the values for racemiza-
tion t½ (from 6‐90 years) show some remarkable,
synthetically useful configurational stability.12
2.5 | General procedures for preparation
of Pd(II) complex (10i)
An oven‐dried reaction vial containing
benzoylphenyl)‐2‐(isopropylamino)acetamide)
9
(N‐(2‐
(0.2
mmol), glycine (5 equiv), PdCl2 (2 equiv), and NaOH (7
equiv) was evacuated and purged with argon three times.
Then, MeOH (4 mL) as solvent were added via syringe at
ambient temperature. Then, the reaction mixture was
stirred for 4 hours at 60°C to 70°C, and then the reaction
was quenched with AcOH (1 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 (1 × 10 mL) and dried
over anhydrous Na2SO4. The solvent was evaporated to
give the crude product, which was purified by flash
chromatography.
While reported in the previous work,10a data provided
detailed and instructive understanding of the chiral nitro-
gen configurational stability in relationship to the reac-
tion solvent, the effect of substituents on the nitrogen as
well as the coordinating metal remained totally
unknown. Thus, drawing inspiration from the success of
2.6 | General procedures for preparation
of Cu(II) complex (10j)
An oven‐dried reaction vial containing 9 (0.2 mmol), gly-
cine (5 equiv), CuSO4.5H2O (2 equiv), and KOH (7 equiv)
was evacuated and purged with argon three times. Then,
MeOH (4 mL) as solvent were added via syringe at ambi-
ent temperature. 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
SCHEME 2 Racemization of Ni(II) complex 5, possessing
stereogenic nitrogen, via discoordinated intermediate 6

4
MEI ET AL.
the previous study,10a we designed a new set of the stereo-
chemical models presented in Scheme 3.
conditions (chiral stationary phases, solvents, tempera-
ture, chiroptical detection) equipped with five different
columns: Pirkle‐type ((S,S)‐Ulmo), cellulose carbamates
(Chiralpak IB and IC), and amylose carbamates
(Chiralpak IA and ID), followed by meticulous optimiza-
tion of the separation conditions for each individual com-
pound. We decided to begin our study with 10a (Figure 1)
containing NH function and linear alkyl N‐n‐Bu group, as
the simplest type of substitution on the stereogenic nitro-
gen. After a series of chiral chromatographic experiments,
we found that reasonably good separation of enantiomers
10a can be achieved on Chiralpak IA column with amy-
lose carbamate stationary phase, using ethanol as an elu-
ent. The HPLC chart of two baseline‐separated
enantiomers 10a, conducted under the optimized condi-
tions, is presented in Figure 1.
Synthesis of compounds 8‐10a‐j was performed similar
10a, 13
to general procedures described earlier.9,
Thus,
commercially available o‐amino‐benzophenones 7 were
chemo‐selectively acylated using bromoacetyl bromide
in acetonitrile to furnish bromo‐amides 8. Isolated and
purified by column chromatography compounds 8 were
reacted with the corresponding secondary of tertiary
amines in the presence of Hünig's base12 to prevent the
quaternization of the amino functionality. Thus, prepared
ligands 9 were heated in methanol with glycine, K2CO3,
NaOH, or KOH (depending on the metal used), as a base,
and source of M(II) ions to furnish racemic M(II) com-
plexes of glycine Schiff bases (R/S)‐10a‐j. Compounds
(R/S)‐10a‐j were purified by column chromatography
and fully characterized.
Using the optimized separation conditions, we con-
ducted preparative separation of enantiomers 10a. Inter-
estingly, while enantiomers (+)‐ and (−)‐10a were
cleanly separated, after the solvent evaporation, the
enantiomeric purity of both (+)‐ and (−)‐10a was about
90% ee, clearly indicating partial racemization during
the isolation procedure. Thus, using the enantiomerically
enriched samples, we performed the enantiomerization
(racemization) energy barriers study. An enantio‐
enriched sample was diluted in ethanol, the solution
was thermostated at 22°C, and its enantiomeric excess
was measured by chiral chromatography every 10
minutes for 1 hour. The first‐order kinetic line for
enantiomerization was drawn with an excellent correla-
tion coefficient. The rate of enantiomerization was
deduced from the slope of the first‐order kinetic line
and gave the following data: kenantiomerisation = 1.15.10−4
s−1 (22°C, ethanol); ΔG≠ = 94.5 kJ/mol (22°C, ethanol).
The present study was initiated using available to us
fully automated screening unit for chiral separation
These data indicated that t racemization for enantio-
½
mers 10a is only 50 minutes at 22°C in ethanol. In other
words, the racemization occurs relatively easy at ambient
temperature; yet, the configurational stability of 10a is
sufficient enough to achieve the goal of this research pro-
ject. For the reference, the data reported for the i‐propyl
SCHEME 3 Synthesis of ligands 9 and chiral glycine Schiff base
M(II) complexes 10a‐j bearing stereogenic nitrogen
containing complex 5 was as follows: kenantiomerization
=
FIGURE 1 Separation of enantiomers
of compound 10a on Chiralpak IA
column; ethanol, 0.8 mL/min, UV 254 nm,
25°C

MEI ET AL.
5
FIGURE 2 Separation of enantiomers
10b and their on‐line racemization;
Chiralpak IA column; ethanol, 0.5 mL/
min, ultraviolet (UV) 254 nm, and CD
390 nm, 45°C
9.05 10−6 s−1 (22°C, ethanol) with the ΔG≠ = 100.8 (kJ/
enantiomerizations. According to the Trapp‐Schurig's
Equation14 developed for dynamic chiral HPLC, the
enantiomerization barrier was calculated from chromato-
graphic parameters, as retention times and height of the
plateau. The experiments were conducted at two different
temperatures and revealed the following kinetic data, at
35°C: kenantiomerisation = 4.61.10−4 s−1 (35°C, ethanol),
ΔG≠ = 95.2 kJ/mol (35°C, ethanol); and at 45°C:
mol) indicated that t racemization for enantiomers 5 is
½
7 hours, indicating some noticeable effect of n‐Bu vs
i‐Pr goups on the configurational stability of the stereo-
genic nitrogen.
Building on this progress, we proceeded with general-
ization of this approach by using compound 10b
(Figure 2) containing the same NH functionally, but with
the benzyl group instead of the linear alkyl substituent.
We found that separation of enantiomers 10b can also
be achieved on Chiralpak IA column under the same
condition as we used for separation of enantiomers of
10a (see the Data S1).
kenantiomerisation = 1.07.10−3 s−1 (45°C, ethanol), ΔG≠
=
96.2 kJ/mol (45 °C, ethanol). Accordingly, the data
recorded for enantiomers of 10b is t1/2 = 30 minutes
(25°C, ethanol), which is quite comparable with the data
obtained for NH‐n‐Bu containing complex 10a.
In this case, however, the enantiomers 10b were not
isolated by preparative HPLC, as we chose to try another
“online” technique to study the racemization kinetics.10c
Thus, the racemization was evidenced during the HPLC
analysis at higher temperature, 45°C, by the occurrence
of a “plateau” between both enantiomers (Figure 2). Each
peak with a chiroptical sign corresponds to enantiomers
that have not undergone any enantiomerization in the
column and the plateau between the two peaks corre-
sponds to molecules that have undergone one or several
Another example of structural generality of this
approach is presented by the example of complex 10c
(Figure 3) containing tertiary amino functionality. In this
case, the best baseline separation of the enantiomers was
achieved on Chiralpak ID column (Rs 1.97); see Data S1
for the HPLC charts and details.
FIGURE 3 Configurational stability of complex 10c
FIGURE 4 Configurational stability of complex 10

6
MEI ET AL.
TABLE 1 Kinetic data (in ethanol) for racemization of complexes
10d‐h
secondary amino group). This line of considerations
prompted us to study complexes 10d,e,g bearing bulky t‐
Bu and new derivatives 10f,h containing i‐Pr groups
(Figure 4).
Complex kenantiomerization ΔG≠
t1/2
10d
6.64.10−6 s−1
(22°C)
101.5 kJ/Mol
(22°C)
14.5 hours
(22°C)
Furthermore, we prepared a series of chloro‐ 10e,f and
nitro‐derivatives 10 g,h, bearing these substituents in the
para‐position to the Ni(II)‐coordinated amide nitrogen
(Figure 4), to briefly explore the electronic factors. For
each of these five compounds 10d‐h, we optimized the
chiral HPLC resolution conditions allowing for a clean
baseline separation of the corresponding enantiomers.
Thus, the following stationary phases were found opti-
mal: Chiralpak ID for 10d, Chiralpak IC for 10,e,g,h,
and Chiralpak IB for 10 f. In each case, the separation
of enantiomers were successfully reproduced on prepara-
tive scale providing approximately 10 mg of the
enantiomerically pure/enriched material to perform
the kinetic studies. The racemization in each case was
studied as described above for complexes 10a and 10c,
following first‐order kinetics experiments. The data
obtained are summarized in Figure 4 and Table 1.
While the number of examples (eight complexes 10a‐h
and 5) is relatively small, one can still notice a clear trend
that steric effects on the amino group have very minor
effect on the stability of these Ni(II) complexes of glycine
Schiff base. By contrast, the electronic effects are of a
much greater role as it follows from the cases of alkyl
substitution on the nitrogen as well as in the derivatives
with the para‐substituents on the aromatic ring. Though
these trends could be anticipated on the basis of general
knowledge about stability of the coordinated com-
pounds,15 the developed method provides the previously
5
1.62.10−5 s−1
(22°C)
99.3 kJ/Mol
(22°C)
6 hours
(22°C)
(ref. 10a)
10e
4.04.10−5 s−1
(22°C)
1.63.10−5 s−1
(22°C)
97.1 kJ/Mol
(22°C)
2.4 hours
(22°C)
10f
99.3 kJ/Mol
(22°C)
6 hours
(22°C)
10 g
10 h
2.22.10−5 s−1
(19°C)
97.5 kJ/Mol
(19°C)
4.3 hours
(19°C)
2.22.10−5 s−1
(19°C)
97.5 kJ/Mol
(19°C)
4.3 hours
(19°C)
Enantiomers of 10c were separated by preparative
chromatography on Chiralpak ID column and remained
stereochemically intact (>98% ee) during isolation and
solvents evaporation, indicating some higher configura-
tional stability, as compared with NH‐n‐Bu derivative
10a. Indeed, the racemization and first‐order kinetics
experiments revealed that in this case, the kenantiomerisation
= 4.11.10−5 s−1 (25°C, ethanol); ΔG≠ = 98.1 kJ/mol
(25°C, ethanol). These data correspond to t1/2 = 140
minutes (25°C, ethanol), which is noticeable greater as
compared with NH type complexes 10a and 10b.
The reason for the observed higher configurational sta-
bility of 10c over 10a,b can be explained by the electron‐
donating effect of the methyl group (vs H) and/or the
overall steric bulk of the tertiary amine moiety (vs
FIGURE 5 Separation of enantiomers
of complex 10i on Chiralpak IA; (ethanol,
0.8 mL/min, UV 254 nm and CD 390 nm)

MEI ET AL.
7
FIGURE 6 Separation of enantiomers
of complex 10j on Chiralpak IB (ethanol,
0.8 mL/min, UV 254 nm, 25°C) and the
online racemization kinetics
unavailable quantitative assessment of the N―Ni(II)
coordination strength.
are sensitive to steric as well as electronic effects and proven
to work well for Ni(II), Pd(II), and Cu(II). Structural sim-
plicity of the model compounds, coupled with high sensitiv-
ity and reliability of experimental procedures bodes well for
further development and application of this approach.
Finally, to show the value of these stereochemical
models for greater potential general applications in areas
related to N‐metal coordination, we decided to measure
the stability of N―Pd(II) and N―Cu(II) bonds. To this
end, we prepared (Scheme 3) the corresponding com-
plexes 10i and 10j (Figures 5 and 6, respectively). As
one can see from Figure 5, very clean baseline separation
of enantiomers of 10i was achieved on Chiralpak IA
using ethanol as an eluent.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No.
21761132021), the IKERBASQUE, Basque Foundation
for Science, and Nanjing Forestry University set‐up fund.
Enantiomers 10i were also separated on the prepara-
tive scale (3 mg each) and isolated in enantiomerically
pure form. Investigation of the kinetics of their racemiza-
tion gave the following data: kenantiomerisation = 9.55.10−6 s
ORCID
−1
(25°C, ethanol); ΔG≠ = 101.7 kJ/mol (25°C, ethanol);
Jianlin Han https://orcid.org/0000-0002-3817-0764
t1/2 = 10 hours (25°C, ethanol). Comparison of the data
obtained for the complex 10e, containing the same ligand,
we can confirm that the N―Pd(II) bond is noticeably
more stable (7 vs 10 hours). While the greater stability of
10i over 10e can be rather expected,15 the quantitative dif-
ference was obtained for the first time in this work. By
contrast, Cu(II) complex 10j was found to be less stable,
as it follows from the online racemization experiments
(Figure 6). The enantiomerization of 10j during chiral
chromatography at 25°C is evidenced by the profile of
the chromatogram. Most of the molecules enantiomerize
during the analysis, giving a very broad central peak.
The following data: kenantiomerisation = 4.62.10−3 s‐1
(25°C, ethanol); ΔG ≠ = 86.4 kJ/mol (25°C, ethanol); t1/2
= 1.25 minutes (25°C, ethanol) indicate that Cu(II) com-
plex 10j is significantly less stable as compared with
Ni(II) (7 hours) 10e and Pd(II) (10 hours) 10i. Again,
while this conclusion can be anticipated,15 the quantita-
tive difference is reported here for the first time.
Vadim A. Soloshonok
4526
https://orcid.org/0000-0003-0681-
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4 | CONCLUSION
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SUPPORTING INFORMATION
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