Facile separation of diastereo-chiral N,N′-diamine ligand via fractional crystallization and demetalation of corresponding Zn(II) complex

Article abstract of DOI:10.1016/j.inoche.2016.01.011

Enantiopure N,N-diamine has been obtained in an economical manner via demetalation of its corresponding dichloro Zn(II) complex, which is separated by fractional crystallization of two diastereomeric Zn(II) complexes. Polymerization of rac-lactide (rac-LA

Full text of DOI:10.1016/j.inoche.2016.01.011

ꢀ
Facile separation of diastereo-chiral N,N -diamine ligand via fractional
crystallization and demetalation of corresponding Zn(II) complex
Saira Nayab, Jong Hwa Jeong
PII:
DOI:
Reference:
S1387-7003(16)30011-9
doi: 10.1016/j.inoche.2016.01.011
INOCHE 6215
To appear in:
Inorganic Chemistry Communications
Received date:
Revised date:
Accepted date:
14 December 2015
21 January 2016
24 January 2016
Please cite this article as: Saira Nayab, Jong Hwa Jeong, Facile separation of
ꢀ
diastereo-chiral N,N -diamine ligand via fractional crystallization and demetalation
of corresponding Zn(II) complex, Inorganic Chemistry Communications (2016), doi:
1
0.1016/j.inoche.2016.01.011
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ACCEPTED MANUSCRIPT
-- Revised Manuscript --
'
Facile Separation of Diastereo-Chiral N,N -diamine Ligand via Fractional Crystallization and
Demetalation of Corresponding Zn(II) Complex
b
a
Saira Nayab and Jong Hwa Jeong *
a
Department of Chemistry and Green-Nano Materials Research Center, Kyungpook National University, 1370 Sankyuk-
dong, Taegu,702-701, Republic of Korea.
b
Department of Chemistry, Shaheed Benazir Bhutto University, Sheringal, Dir Upper, Khyber Pakhtunkhwa, Republic of
Pakistan
Tel. (82)-53-950-6343
Fax: (82)-53-950-6330
E-mail: jeongjh@knu.ac.kr
0

ACCEPTED MANUSCRIPT
'
Facile Separation of Diastereo-Chiral N,N -diamine Ligand via Fractional Crystallization and
Demetalation of Corresponding Zn(II) Complex
b
a
Saira Nayab and Jong Hwa Jeong *
a
Department of Chemistry and Green-Nano Materials Research Center, Kyungpook National University, 1370 Sankyuk-
dong, Taegu,702-701, Republic of Korea.
b
Department of Chemistry, Shaheed Benazir Bhutto University, Sheringal, Dir Upper, Khyber Pakhtunkhwa, Republic of
Pakistan
Abstract
Enantiopure N,N-diamine has been obtained in an economical manner via demetalation of its corresponding
dichloro Zn(II) complex, which is separated by fractional crystallization of two diastereomeric Zn(II) complexes.
Polymerization of rac-lactide (rac-LA) initiated by diisopropoxide derivative proceeds rapidly at room temperature in a
living fashion to yield heterotactic polylactide (PLA) with P = 0.90.
r
Keywords: Enantiopure zinc complexes, X-ray structure, Ring-opening polymerisation, Double active site catalysts,
Heterotactic-enriched polylactide
Chiral vicinal diamines are important structures in asymmetric catalysis because of their utility and
1
-3
enantioselectivity for a variety of reactions. The diamines, especially those with C -symmetry, have considerable
2
importance, since they are used in a wide range of organometallic catalysts and organocatalysts to provide asymmetry for
4
reactions such as hydrogenations, oxidations, ring-openings, and carbon-carbon bond-formations. Furthermore, diamine
functionality appears in various compounds showing a broad spectrum of biological activities, including antibacterial,
5
anticancer, and antihypertensive. Undeniably, numerous enantiopure diamines that require elaborate synthesis and/or are
6
expensive have been reported. One method for the synthesis of enantiopure N,N-diamines is the grafting of alkyl moieties
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at imine carbons, which results in various diastereomers. The ratios of these diastereomeric components may vary
depending on the reaction conditions. The separation of these diastereomers to obtain enantiopure ligands in appreciable
8
amounts for various asymmetric reactions is a crucial step. To date this area of separation is dominated by traditional
column chromatography with impractical amounts of enantiopure ligands. To the best of our knowledge, no report has
explored enantiopure ligand generation by demetalation of enantiopure metal complexes, which have been obtained in a
very economic manner by fractional crystallization from a mixture of two diastereomeric complexes. Herein, the
0

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preliminary results of a facile separation technique based on the fractional crystallization of two diastereomeric complexes
and subsequent demetalation of the major enantiopure Zn(II) complex to obtain enantiopure ligand in facile yield and high
purity, are reported. In addition the catalytic application in ROP of rac-LA has been performed keeping in view the
9-13
growing interest in the development of stereospecific catalysts to obtain PLA
owing to PLA's biodegradability,
14,15
biocompatibility and the possibility of deriving monomer from renewable resources.
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8
Alkylation of 1 with MeLi resulted in two diastereomers of the secondary diamine 2, which could not be
1
separated by column chromatography even after several trials. Analysis of 2 by H-NMR spectroscopy clearly showed
two quartets for methine protons at  3.78 and 3.69 for two diastereomers. The grafting of alkyl groups at the ethylene
backbone showed distereoselectivity for RR- compared to SS- and RS- diastereomers at a ratio of 1:0.4:0. Lacking a
readily available separation process, crude ligand 2 was subjected to the next reaction without separation. Ligation of 2a
1
and 2b with ZnCl resulted in a mixture of two diastereomeric Zn(II) complexes in a 1:0.3 ratio as confirmed by H-NMR
2
1
(
Fig. 1b). The enantiopure Zn(II) complexes, 3a and 3b were separated by fractional crystallization in EtOH. The H-
NMR (Fig. 1c) spectrum clearly showed a sextet at  4.15 for the methine proton of pendent chiral amine moieties.
Demetalation of 3a resulted in enantiopure ligand 2a (Fig. 1d) in quantitative yields (Scheme 1). Structural
characterizations of enantiopure ligand 2a and the Zn(II) complexes 3a and 3b, were investigated by IR and elemental
1
13
analyses, coupled with H and C NMR spectroscopy. As RR(R,R) and SS(R,R) are diastereomers and have different
physical properties and complex 3b was more soluble in EtOH, practical amount of solid 3b was not obtain compared to
3
a.
Complex 3a crystallized out as a single nuclear complex with a distorted tetrahedral geometry. The plane angle
between Cl-Zn-Cl and N-Zn-N was found to be 83.76(5)º. The bond lengths and angles did not vary much from known
17-19
values (ESI Table S2).
Enantiomeric 1,2-diamine with chiral backbone blocked nitrogen atoms of secondary amines in
a five membered ring in a homochiral fashion. The hydrogen atoms of the chiral carbons and nitrogens were in a head-to-
tail conformation (Fig. 2). Furthermore the resultant five membered chelate ring Zn-N-C-C-N was solely in a 
conformation.
Ring opening polymerization studies of rac-LA were carried out using diisopropoxide derivatives, generated in
situ, of 3a, which polymerizes rac-LA at room temperature with very high activity. The monomer was completely
1
converted to PLA within 3 min; 94% conversion was observed after 2 min, as confirmed by H-NMR analyses. The
polymerization was well processed with the diisopropoxide derivative of 3a, yielding PLA which was highly enriched-
heterotactic (P = 0.90). The M = 7,010 determined by GPC was agreed well with a half of predicted values, which meant
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n
the catalyst possessed a dual active site. The narrow PDI (1.33) and linear correlation between M and percent conversion
n
1
(
by H-NMR) are indicative of a living polymerization. The polymer chain was end-capped with an isopropoxide [-
1
C(=O)CH(CH ) ] group at one end and a hydroxyl group [-CHMe-(OH)] at the other, as determined from the H-NMR
3
2
spectrum of the resultant PLA, M = 7,500 which is a similar value by GPC. The observed results suggest that
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polymerization mediated by alkoxide Zn(II) complex may be initiated by a coordination insertion mechanism.
Reference experiments using LiOCHMe in ROP of rac-LA under the same experimental conditions resulted in PLA in a
2
quantifiable yield but at a slow rate and low stereoselectivity (P = 0.55). Heterotactic-enriched PLA using in situ
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generated diisopropoxide derivative of enantiopure 3a might be resulted by chain end control mechanism with unclear
24,25
assist of the stereogenic centers, which is consistent with previously observed results.
Furthermore, the amount of 3b
was not optimum to carry out the polymerization with the mentioned complex. Thus, the observed stereoselectivity arises
from the homochiral ligand architecture, which provided better control over the polymerization process and significantly
influenced the stereoselectivity of the resulting PLA.
In conclusion, we developed a facile methodology to obtain an enantiopure ligand in appreciable amounts via
demetalation of its dichloro Zn(II) complex, which was separated by fractional crystallization from mixture of
diastereomeric complexes. Highly heterotactic PLA was obtained at room temperature from rac-LA using an in situ
catalytic species of 3a within 3 min. The polymerization proceeded in a living manner to yield PLA with high molecular
weight and a narrow molecular weight distribution. Efforts to elucidate the mechanistic information in detail are
underway. This enantiopure ligand, apart from its economical and facile separation, can be further utilized as a chiral
auxiliary in various metal catalyzed transformations.
Acknowledgements
This research was supported by Basic Science Research Program through the National Research Foundation of Korea
(
NRF) funded by the Ministry of Education, Science and Technology (NRF-2011-0023197).
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834.
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Ph
Ph
Ph
O
NH
N
NH
O
MeLi
THF, -78 C
HO
O
o
+
MgSO , CH Cl , RT
Deareated H O
4
2
2
2
NH
N
NH
H N
2
d
e
il
Ph
a
F
n
o
Ph
Ph
ti
Ph
a
r
e
p
2 a
2 b
e
S
1
n
m
lu
o
C
Ph
NH
EtOH ZnCl2
NH
N
C
a
ion
N
.
Ph
q
lat
a
/
a
2 a
C
t
e
M
m
e
D
Ph
Ph
Ph
H
H
N
H
H
N
Cl
Cl
Cl
N
N
Cl
Cl
Fractional crystallization
in EtOH
Zn
Zn
Zn
Cl
N
N
H
H
Ph
Ph
Ph
3 a
3 b
3
a
Scheme 1
4

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1
Fig. 1. Comparative view of H NMR clearly demonstrating the methine protons of the ligand architechture in (a) 2
(
b) 3a and 3b (c) 3a and (d) 2a.
C17
C5
C8
C9
C18
C16
C4
C6
C15
C19
C10
C3
C7
C11
C20
N2
C12
C2
C14
C13
N1
Zn
Cl1
C1
Cl2
Fig 2. ORTEP diagram of the molecular structure of complex 3a. Thermal ellipsoids are drawn at the 30% probability
level. All hydrogens and free solvent molecules are omitted for clarity.
5

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Graphical Abstract - Synopsis
'
Facile Separation of Diastereo-Chiral N,N -diamine Ligand via Fractional Crystallization and
Demetalation of Corresponding Zn(II) Complex
b
a
Saira Nayab and Jong Hwa Jeong *
a
Department of Chemistry and Green-Nano Materials Research Center, Kyungpook National University, 1370 Sankyuk-
dong, Taegu,702-701, Republic of Korea.
b
Department of Chemistry, Shaheed Benazir Bhutto University, Sheringal, Dir Upper, Khyber Pakhtunkhwa, Republic of
Pakistan
Herein, we have reported the facile and economical way to obtain enantiopure N,N-diamine via demetalation
of its corresponding dichloro Zn(II) complex, which is obtained by fractional crystallization of two
diastereomeric Zn(II) complexes. Diisopropoxide Zn(II) complex generated is situ polymerize racemic lactide
within 3 min to yield heterotactic PLA with P = 0.90.
r
6

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Graphical Abstract - Pictogram
'
Facile Separation of Diastereo-Chiral N,N -diamine Ligand via Fractional Crystallization and
Demetalation of Corresponding Zn(II) Complex
b
a
Saira Nayab and Jong Hwa Jeong *
a
Department of Chemistry and Green-Nano Materials Research Center, Kyungpook National University, 1370 Sankyuk-
dong, Taegu,702-701, Republic of Korea.
b
Department of Chemistry, Shaheed Benazir Bhutto University, Sheringal, Dir Upper, Khyber Pakhtunkhwa, Republic of
Pakistan
Ph
Ph
Ph
H
N
Cl
NH
H
Zn
Ph
N
N
Cl
Cl
Cl
Zn
Ph
N
H
NH
H
Ph
Ph
(
R)
ZnCl2
H
N
N
Cl
Cl
(
R)
Zn
(
R)
H
(
R)
Ph
i
2
LiO Pr2
O
O
O
O
O
O
n
n
O
*
+
O
O
O
O
O
*
O
n
O
O
L-Lactide
O
Heterotactic PLA (Pr = 0.90)
D-Lactide
7

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Research Highlights
•
The facile way to obtain enantiopure N,N-diamine via demetalation of its corresponding dichloro Zn(II)
complex, which is obtained by fractional crystallization of two diastereomeric Zn(II) complexes.
•
•
The diisoproxide derivatives polymerised rac-LA in living manner.
The resultant PLA was found to be heterotactic with P up to 0.90.
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8