Titanium complexes bearing 2,6-Bis(o-hydroxyalkyl)pyridine ligands in the ring-opening polymerization of L-Lactide and ε-caprolactone

Article abstract of DOI:10.1016/j.polymer.2020.122860

A series of titanium (Ti) compounds bearing 2,6-bis(o-hydroxyalkyl)pyridine ligands were synthesized and investigated as catalysts for the ring-opening polymerization of ε-caprolactone (CL) and L-lactide (LA). The Ti complexes with electron-withdrawing gr

Full text of DOI:10.1016/j.polymer.2020.122860

Journal Pre-proof
Titanium complexes bearing 2,6-Bis(o-hydroxyalkyl)pyridine ligands in the ring-
opening polymerization of L-Lactide and ε-caprolactone
Feng-Jie Lai, Tsai-Wen Huang, Yu-Lun Chang, Heng-Yi Chang, Wei-Yi Lu, Shangwu
Ding, Hsuan-Ying Chen, Chien-Chih Chiu, Kuo-Hui Wu
PII:
S0032-3861(20)30687-X
DOI:
https://doi.org/10.1016/j.polymer.2020.122860
JPOL 122860
Reference:
To appear in: Polymer
Received Date: 27 May 2020
Revised Date: 23 July 2020
Accepted Date: 26 July 2020
Please cite this article as: Lai F-J, Huang T-W, Chang Y-L, Chang H-Y, Lu W-Y, Ding S, Chen H-Y,
Chiu C-C, Wu K-H, Titanium complexes bearing 2,6-Bis(o-hydroxyalkyl)pyridine ligands in the ring-
opening polymerization of L-Lactide and ε-caprolactone, Polymer (2020), doi: https://doi.org/10.1016/
j.polymer.2020.122860.
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CRediT author statement
Feng-Jie Lai: Writing-Reviewing and editing
Tsai-Wen Huang: Ti complexes synthesis and characterization, polymerization
Heng-Yi Chang: Ti complexes synthesis, polymerization, polymer analysis
Wei-Yi Lu: X-ray Data
Yu-Lun Chang: X-ray Data
Shangwu Ding: Writing-Reviewing and editing,
Hsuan-Ying Chen: Conceptualization, Writing-Original
Chien-Chih Chiu: Writing-Original
Kuo-Hui Wu: DFT calculation

Graphic Abstract

Titanium Complexes Bearing 2,6-Bis(o-hydroxyalkyl)pyridine Ligands in the Ring-Opening
Polymerization of L-Lactide and -Caprolactone
ε
Feng-Jie Lai,ab‡ Tsai-Wen Huang,c‡ Yu-Lun Chang,c Heng-Yi Chang,c Wei-Yi Lu,c Shangwu Ding,cd
Hsuan-Ying Chen,cde* Chien-Chih Chiu,f* Kuo-Hui Wugh*
a Department of Dermatology, Chi Mei Medical Center, Tainan, Taiwan, R.O.C.
b
Center for General Education, Southern Taiwan University of Science and Technology, Tainan,
Taiwan, R.O.C.
c Department of Medicinal and Applied Chemistry, Drug Development and Value Creation Research
Center, Kaohsiung Medical University, Kaohsiung, Taiwan, 80708, R.O.C.
d Department of Chemistry, National Sun Yat-sen University, Kaohsiung, Taiwan, 80424, R.O.C.
e
Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708,
Taiwan, R.O.C.
f Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C.
g Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033,
Japan.
h Department of Chemistry, Tamkang University, Tamsui 251, Taiwan, R.O.C.
Abstract
A series of titanium (Ti) compounds bearing 2,6-bis(o-hydroxyalkyl)pyridine ligands were
synthesized and investigated as catalysts for the ring-opening polymerization of ε-caprolactone (CL)
and L-lactide (LA). The Ti complexes with electron-withdrawing groups in pyridine rings or steric
bulky groups in hydroxymethyl groups reduced the catalytic activity in CL and LA polymerizations,
and MeLPh-TiOPr2 exhibited the highest catalytic activity ([CL] = 0.5 M, [CL]:[Cat] = 100:8, 60 oC,
7.5 h, conversion = 93%; [LA] = 0.5 M, [LA]:[Cat] = 100:8, 60 oC, 3.5 h, conversion = 98%). The
density functional theory calculation results revealed that CL interacted with the ligand through
weak hydrogen bonds, and then approached the Ti center. After being attacked by isopropyl oxide,
the carbonyl group of CL bonded to the Ti center. After the rearrangement and ring opening of CL
ring, CL was converted to poly-ε-caprolactone.
1

Keywords: Titanium complex, ε-Caprolactone, L-Lactide, Ring-opening polymerization
________________________________________________________________________________
* Corresponding Author: Hsuan-Ying Chen, E-mail: hchen@kmu.edu.tw
Chien-Chih Chiu, E-mail: cchiu@kmu.edu.tw
Kuo-Hui Wu: wukuohui@chem.s.u.-tokyo.ac.jp
Tel.: +886-7-3121101-2585, Fax: +886-7-3125339
1.0. Introduction
Ligands are essential in organometallic catalysts because they improve the catalytic reactivity
and selectivity for catalysis through steric, electronic, and chelating effects. Pincer ligands,[1-6]
common type of ligand, bond securely to three neighboring coplanar sites in a meridional
a
configuration. The rigidity of the pincer-metal interaction results in high thermal stability in the
resultant complexes. Pincer complexes are used in catalytic applications such as addition to
olefins,[7, 8] C-C[9-14] and C-S[15] cross-coupling, cycloisomerization,[16, 17] hydrogenation of
ketones and aldehydes,[18, 19] hydrogenation of ester and amide,[20-22] hydrophosphination,[23,
24] hydrosilylation of acetophenone,[25, 26] olefin polymerization,[27-29] and ring
opening-polymerization of cycloesters.[30] Recently Zaitsev[30] reported the synthesis of pincer Al
complexes bearing pyridine-substituted alcohols (Figure 1a) and their application in ε-caprolactone
(CL) and L-lactide (LA) polymerization and revealed that Al complexes were moderately active in a
controlled or an immortal LA polymerization and that steric bulky substituents on the ligands
increased the catalytic activity. Suzuki29 reported the synthesis of pincer Ti complexes bearing
pyridine-substituted alcohols (Figure 1b) and their application in ethylene polymerization. The
polymerization results revealed that the order of the activity was R = i-Pr > t-Bu > Et, and the
molecular mass of the polymer was in the order R = i-Pr > Et > t-Bu. In addition to Al catalysts, Ti
complexes[31-42] were used as catalysts in polymerization of cyclic esters. According to these
reports, Ti complexes bearing 2,6-bis(hydroxyalkyl)pyridines ligands should be effective in CL and
LA polymerizations, and substituents (R) should influence the controllability of Ti catalysts. Herein,
we synthesized a series of 2,6-bis(hydroxyalkyl)pyridines ligands and their titanium alkoxide
complexes (Figure 2). The ROP of CL and LA were studied to investigate the steric effect on ROP.
2

(a)
(b)
R
R
O
Ph
N
Ph
Cl
Cl
O
Al
O
Ti
N
O
X
R
R
R
R
X = CH2, R = Ph
X = CH2, R = CH3
X = (CH2)2, R = Ph
R = Et, i-Pr, t-Bu,
Figure 1. Pincer metal complexes bearing pyridine-substituted alcohols: (a) Al complexes30
for ROP and (b) Ti complexes29 for olefin polymerization
1, n-BuLi /THF/ 0 oC
R1
O
R1
N
2,
/-78 oC
2R R2
H2O2/acetic acid
N
N
2R
R2
O
refluxed at 100 oC
HO
3, n-BuLi /THF/ 0 oC
OH
2R OH HO R2
4,
O
N
/-78 oC
HLMeO-H
2R R2
R1 = H, R2 = CH3, HLMe-H
R1 = H, R2 = Ph, HLPh-H
R1 = CH3, R2 = Ph, MeLPh-H
HO
OH
1/4 Ti(OPr)4
i
1/2
Ti(O Pr)4
Ti(OiPr)4
N
R1
N
O
O
Ti
O
O
N
O
O
R2
R2
2R
2R
O
O
Ti
O
O
O
O
O
O
N
Ti
Ti
N
Ti
N
O O
O
O
Ti
N
HLMe-TiOPr2
HLPh-TiOPr2
MeLPh-TiOPr2
O
O
(HLMeTi-O)4
HLMe2-Ti
Figure 2. Preparation of 2,6-bis(hydroxyalkyl)pyridines ligands and associated Ti compounds
2.0. Results and Discussion
2.1. Synthesis and Characterization of 2,6-bis(hydroxyalkyl)pyridines ligands and
3

associated Ti Complexes.
HLMe-H [43, 44] and HLPh-H30 were prepared according to techniques provided in the literature.
MeLPh-H was synthesized using a method similar to that of the synthesis of HLPh-H. In this case,
2,4,6-collidine was used to replace 2,6-lutidine. HLMeO-H was synthesized from the reaction of
HLMeO-H and H2O2 in acetic acid. In the reaction, HLMe-H, HLPh-H, and MeLPh-H reacted with a
stoichiometric quantity of titanium isopropoxide in toluene to produce a moderate yield of Ti
compounds (HLMe-TiOPr2, HLPh-TiOPr2, and MeLPh-TiOPr2, respectively) (Figure 2).
Furthermore, HLMeO-H reacted with a stoichiometric quantity of titanium isopropoxide in toluene to
produce (HLMeTi-O)4. Another method of producing (HLMeTi-O)4 is through the reaction of
HLMe-TiOPr2 with a stoichiometric quantity of H2O. According to the 1H and 13C nuclear magnetic
resonance (NMR) spectra and elemental analysis (EA) data, when two equivalents of titanium
isopropoxide reacted with one equivalent of HLMe-H, the resulting product was HLMe2-Ti.
The X-ray structure of HLPh-TiOPr2 (CCDC 2005807, Figure 3) revealed the distorted
trigonal bipyramidal geometry (τ = 0.84)[45] with two terminal isopropoxides. The axial angle of
N(1)-Ti(1)-O(3) was 172.59(8)o and the equatorial angles between O(1)-Ti(1)-O(2),
O(2)-Ti(1)-O(4), and O(4)-Ti(1)-O(2) were 115.06(9)o, 121.88(10)o, and 118.24(10)o, respectively.
The bond of Ti(1)-O(3) in the axial position was 1.8392(19) Å, and the bonds of Ti(1)−O(1),
Ti(1)−O(2), and Ti(1)−O(4) (in the equatorial position) were 1.8366(19) Å, 1.8394(18) Å, and
1.783(2) Å). The structure of (HLMeTi-O)4 (CCDC 2005806, Figure 4) comprises a tetramer of five
coordinated Ti complexes with distorted trigonal bipyramidal geometry (τ = 0.94) and four bridging
oxygen atoms connected with four Ti atoms, which form an eight-membered ring structure.
4

Figure 3. Molecular structure of HLPh-TiOPr2 with 20% probability ellipsoids (all hydrogen atoms
were omitted for clarity). Selected bond lengths (A) and bond angles (deg): Ti(1)−O(1) 1.8366(19),
Ti(1)−O(2) 1.8394(18), Ti(1)−O(3) 1.8392(19), Ti(1)−O(4) 1.783(2), Ti(1)−N(1) 2.355(2);
O(3)−Ti(1)−N(1) 172.59(8), O(4)−Ti(1)−O(1) 121.88(10), O(4)−Ti(1)−O(2) 118.24(10),
O(1)−Ti(1)−O(2) 115.06(9), Ti(1)−O(3)−C(14) 127.61(17), Ti(1)−O(4)−C(39) 164.5(2).
Figure 4. Molecular structure of (HLMeTi-O)4 with 10% probability ellipsoids (all hydrogen atoms
were omitted for clarity). Selected bond lengths (A) and bond angles (deg): Ti(1)−O(1) 1.8433(17),
Ti(1)−O(2) 1.8351(17), Ti(1)−O(3) 1.8392(19), Ti(1)−O(4) 1.783(2), Ti(1)−N(1) 2.363(2);
O(4)−Ti(1)−N(1) 175.71(7), O(3)−Ti(1)−O(1) 119.49(8), O(3)−Ti(1)−O(2) 119.46(8),
5

O(1)−Ti(1)−O(2) 115.27(8), Ti(1)−O(3)−Ti(2) 162.95(11), Ti(1)−O(4)−Ti(2A) 169.66(10).
2.2. Polymerization of CL and LA.
In this experiment, the polymerizations of CL and LA using Ti complexes as an initiator in
toluene were investigated under nitrogen (Tables 1 and 2). As observed from entries 1-5 in Table 1,
H
the catalytic order of Ti complexes for CL polymerization was MeLPh-TiOPr2 > LMe-TiOPr2 >
H
HLPh-TiOPr2 > LMe2-Ti > (HLMeTi-O)4. The results revealed that MeLPh-TiOPr2 had a higher
H
catalytic activity than LMe-TiOPr2 because the electron donating substituents in the pyridyl ring,
such as the methyl group, enhanced catalytic activity, whereas HLPh-TiOPr2 with the bulky
substituents in the hydroxyethan-1-olate group, such as the phenyl group, reduced catalytic activity
compared with HLMe-TiOPr2. Electron donating substituents can enhance pyridine coordination and
weaken the Ti-isopropyl oxide bond to ease monomer initiation by isopropyl oxide. The steric
bulky substituent in the hydroxyethan-1-olate group can block monomer coordination and reduce
catalytic activity. (HLMeTi-O)4 exhibited the lowest catalytic activity because of a crowded catalytic
Ti center and weak initiators (BnOH) with lower nucleophilicity than isopropyl oxide. The LA
polymerization results (Table 2) from using these Ti complexes were similar to those of CL
polymerization, with the exception of HLMe2-Ti, which had the lowest catalytic activity.
MeLPh-TiOPr2 with the highest catalytic activity was used as a catalyst to test the controllability of
PLA and PCL. Polymerization with various ratios of monomers catalyzed by MeLPh-TiOPr2 was
studied to identify the properties of these polymers (entries 6-11 of Table 1, and 6-12 in Table 2,
and Figure 5). The results revealed that MeLPh-TiOPr2 exhibited higher controllability with similar
1
values of MnCal, MnNMR, and MnGPC and narrow dispersity (Đ, less than 1.26). The H NMR
spectrum of PCL (Figure S23) and PLA (Figure S24) revealed that isopropyl oxide initiated the
monomers to form the polymer end chain.
6

Table 1. Polymerization of CL using various Ti complexes as catalysts.
b
a
c
Entry
1d
Catalyst
[CL]:[Cat]:[BnOH]
HLMe-TiOPr2
100:8:0
Time Conv.a MnCal MnNMR MnGPC
Đ c
kobs (h-1)
[error]k
(h)
11
(%)
93
800
800
800
900
800
5800
1100
1000
1200
1100
1200
5800
900
900
1.11
1.12
1.08
1.31
1.34
1.09
0.238 [6]
2d
HLPh-TiOPr2
20
7.5
14
5.5
8
94
93
53
50
99
99
73
50
99
99
0.141 [5]
0.356 [8]
0.062 [2]
0.117 [7]
100:8:0
3d
MeLPh-TiOPr2
100:8:0
900
4e
(HLMeTi-O)4
1000
1100
6400
100:2:8
HLMe2-Ti
5e
100:8:8
MeLPh-TiOPr2
j
6f
-
100:1:0
j
7g
MeLPh-TiOPr2
200:1:0
8
11500 11300
12500 13000
11500 12800
17200 17300
22900 23400
11900 1.23
14000 1.16
13300 1.23
18900 1.25
23000 1.26
-
j
8h
MeLPh-TiOPr2
8
-
300:1:0
j
9i
MeLPh-TiOPr2
400:1:0
8
-
j
10h
11i
MeLPh-TiOPr2
16
16
-
300:1:0
j
MeLMe-TiOPr2
400:1:0
-
a Obtained from 1H NMR analysis. b Calculated from the molecular weight of monomer × [CL]0/ 2[Cat]0 × conversion yield + Mw(PriOH) (entries
1-3 and 6-11). Calculated from the molecular weight of monomer × [CL]0/ [BnOH]0 × conversion yield + Mw(BnOH) (entries 4-5). c Obtained
from GPC analysis and calibrated using the polystyrene standard. Values of MnGPC are the values obtained from GPC times 0.56 for PCL. d Reaction
condition: toluene (5 mL), [CL] = 0.5 M, [CL] : [Cat] = 100 : 8, 60 oC. e Reaction condition: toluene (5 mL), [CL] = 0.5 M, [CL] : [Cat] : [BnOH] =
100 : 2 : 8, 60 oC. f Reaction condition: no solvent, MeLPh-TiOPr2 = 0.1 mmol, CL = 10 mmol, 100 oC. g Reaction condition: no solvent, MeLPh-TiOPr2 =
0.1 mmol, CL = 20 mmol, 100 oC. h Reaction condition: no solvent, MeLPh-TiOPr2 = 0.1 mmol, CL = 30 mmol, 100 oC. iReaction condition: no solvent,
MeLPh-TiOPr2 = 0.1 mmol, CL = 40 mmol, 100 oC. j kobs do not be calculated. k kobs is obtained by the first-order rate law for the consumption of [CL].
[error] is standard deviation from the kinetic study.
7

Table 2. Polymerization of LA using various Ti complexes as catalysts.
b
c
Entry
1d
Catalyst
[LA]:[Cat]:[BnOH]
HLMe-TiOPr2
100:8:0
Time Conv.a MnCal MnGPC
Đ c
kobs (h-1)
[error]l
(h)
4
(%)
96
900
900
1200
1100
1100
1400
1100
8100
1.17 0.924 [27]
1.11 0.564 [12]
1.11 1.262 [44]
1.12 0.431 [7]
2d
HLPh-TiOPr2
6
3.5
4
96
98
80
51
99
99
72
84
99
99
99
100:8:0
3d
MeLPh-TiOPr2
100:8:0
1000
1500
1000
7300
4e
(HLMeTi-O)4
100:2:8
HLMe2-Ti
5e
14
1
1.10 0.070 [1]
100:8:8
MeLPh-TiOPr2
k
6f
1.03
-
-
-
-
-
-
-
100:1:0
k
k
k
k
k
k
7g
MeLPh-TiOPr2
200:1:0
3
14500 16600 1.10
15600 19900 1.11
18200 21100 1.23
21700 21700 1.25
28900 28900 1.22
36100 36500 1.21
8h
MeLPh-TiOPr2
1
300:1:0
9i
MeLPh-TiOPr2
400:1:0
3
10h
11i
12j
MeLPh-TiOPr2
6
300:1:0
MeLMe-TiOPr2
400:1:0
12
12
MeLMe-TiOPr2
500:1:0
a Obtained from 1H NMR analysis. b Calculated from the molecular weight of monomer × [LA]0/ 2[Cat]0 × conversion yield + Mw(PriOH) (entries
1-3 and 6-12). Calculated from the molecular weight of monomer × [LA]0/ [BnOH]0 × conversion yield + Mw(BnOH) (entries 4-5). c Obtained
from GPC analysis and calibrated using the polystyrene standard. Values of MnGPC are the values obtained from GPC times 0.58 for PLA. d Reaction
condition: toluene (5 mL), [LA] = 0.5 M, [LA] : [Cat] = 100 : 8, 60 oC. e Reaction condition: toluene (5 mL), [LA] = 0.5 M, [LA] : [Cat] : [BnOH] =
100 : 2 : 8, 60 oC. f Reaction condition: no solvent, MeLPh-TiOPr2 = 0.1 mmol, LA = 10 mmol, 130 oC. g Reaction condition: no solvent, MeLPh-TiOPr2 =
0.1 mmol, LA = 20 mmol, 130 oC. h Reaction condition: no solvent, MeLPh-TiOPr2 = 0.1 mmol, LA = 30 mmol, 130 oC. Reaction condition: no
solvent, MeLPh-TiOPr2 = 0.1 mmol, LA = 40 mmol, 130 oC i. j Reaction condition: no solvent, MeLPh-TiOPr2 = 0.1 mmol, LA = 50 mmol, 130 oC. k kobs
do not be calculated. l kobs is obtained by the first-order rate law for the consumption of [CL]. [error] is standard deviation from the kinetic study.
8

(A)
(B)
25000
20000
15000
10000
5000
0
5
4
3
2
1
40000
5
4
3
2
1
35000
30000
25000
20000
15000
10000
5000
0
y = 716.11 + 117.40 x
R2 = 0.996
y = 905.68 + 143.56 x
R2 = 0.998
0
50
100
150
200
0
50
100
150
200
250
[CL] × conv. /2[Ti]
[LA] × conv./ 2 [Ti]
Figure 5. Linear plot of (A) MnGPC versus ([CL]0 × conv. / [MeLPh-TiOPr2]0) and (B) MnGPC versus
([LA]0 × conv. / [MeLPh-TiOPr2]0) with polydispersity indexes indicated by blue closed square
[entries 3, 6-11 for (A); entries 14, 17, 20-23 for (B), Table 1]
Kinetic Studies of the Polymerization of CL and LA catalyzed by HLMe-TiOPr2
Kinetic studies were performed at 100 oC with respect to the ratio of [M]0/[HLMe-TiOPr2] ([CL]
= 0.5 M and [LA] = 0.5 M in CDCl3 [1 mL] in a sealed NMR tube), as depicted in Tables S3-S4
and Figures S2-S5. The preliminary results indicated a first-order dependency on [CL] and [LA]
(Figures S2 and S4). By plotting kobs versus [HLMe-Ti(OPr)2] with HLMe-Ti(OPr)2 order of 1, kapp
values of 0.072 and 0.354 (M-1min-1) were discovered for CL and LA (Figures S3 and S5),
respectively. The polymerizations of CL and LA using HLMe-Ti(OPr)2 at 100 °C demonstrated the
following rate law:
d[CL]/dt = 0.072 × [CL][HLMe-Ti(OPr)2]
d[LA]/dt = 0.354 × [LA][HLMe-Ti(OPr)2]
Density Functional Theory Study of the Polymerization Mechanism Catalyzed by
9

HLPh-Ti(OPr)2
The reaction mechanism of cyclic ester ROP catalyzed by titanium catalysts was studied using
density functional theory (DFT) calculation under the B3LYP level. The basis set for Ti was
LanL2DZ, and that for H, C, N and O atoms was 6-31G(d). The structures of reaction intermediates
and transition states in the calculation were based on the X-ray structure of HLPhTiOPr2. CL was
selected as the monomer in the theoretical study.
To initiate the ROP reaction, a monomer molecule must be bounded on the catalyst to activate its
ester group or to draw the group close to the alkyl oxide initiator. On the base of this consideration,
the catalyst can activate CL through three reaction pathways (Figure 6). In the first pathway, CL
approaches the complex from the space above the HLPh ligand, which generates intermediate I. In
the second pathway, axial isopropyl oxide is reorganized to equatorial positions, and CL coordinates
on the axial position trans to HLPh pyridine to form intermediate II. In the third pathway, the
monomer enters the equatorial sites trans to hydroxyethan-1-olate groups of HLPh to form
intermediate D.
The central Ti of the optimized structure of intermediate I (Figure S16) exhibited a trigonal
bipyramidal geometry, which is similar for that of HLPhTiOPr2, in which one OPr ligand and HLPh
pyridine ligands coordinated on the axis positions, and two HLPh hydroxyethan-1-olate ligands and
the other OPr are on the equatorial positions. CL bounded above HLPh through weak interactions
with the phenyl rings of HLPh. The distance between the CL carbonyl oxygen (Ocarb) and the central
Ti atom was 4.422 Å, which was considerably longer than those of Ti-Ocarb bonds of other Ti-ester
complexes (2.02 to 2.10 Å), indicated that CL did not directly coordinate on the Ti atom.[46-48]
However, the distances between Ocarb and two ortho hydrogen atoms (Hortho) of the two equatorial
phenyl rings of HLPh were 2.496 and 2.497 Å, respectively, and the distance between ester oxygen
(Oring) and Hortho of an axial phenyl ring of HLPh was 2.644 Å. These three distances were smaller
than the sum of the van der Waals radii of hydrogen and oxygen atoms (approximately 2.9 Å),
which indicated that these Hortho atoms had direct attraction interaction with Ocarb and Oring.[49]
10

These three interactions are regarded to be the major forces that bind CL to the catalyst. Moreover,
the distance between the carbonyl carbon atom (Ccarb) of CL and the oxygen atom (OPr) of the axial
alkoxide ligand was 3.728 Å, and Ccarb directly faced axial OPr. This conformation facilitated the
addition reaction of axial OPr to Ccarb. The free energy of intermediate I was 18.2 kcal mol-1,
assuming the sum of the free energy of HLPhTiOPr2 and free CL was 0 kcal mol-1. (Figures 7 and 8)
The optimized intermediate II has an octahedral coordination geometry for titanium (Figure S17).
All four alkoxide ligands were in the equatorial plane. The CL coordinated on the axial site opposite
to the pyridine ligand. The Ti-Ocarb bond length was 2.220 Å and the Ti-Ocarb-Ccarb angle was
135.78o. The bond length was approximately 0.1 Å longer and the bond angle was approximately
15o smaller than those of other Ti-ester complexes (2.02 to 2.1 Å, 149 to 153o), which indicated that
this Ti-Ocarb bond was slightly weaker than those of other Ti-ester complexes.[46-48] The structure
of II was different from that of I such that no OPr ligands directly faced the carbonyl group, which
smoothened the addition reaction. Although a stable optimized structure of intermediate II occurred
in this pathway, its free energy was 34.7 kcal mol-1, which is considerably higher than that of I
because all bulky ligands were reorganized to crowded equatorial sites, which created high
repulsive forces. In the third pathway, CL did not bond on an equatorial coordination site or have
any weak interaction with the catalyst because of the crowding of the equatorial space.
After CL bonded to the catalyst, OPr reacted with Ccarb to form a hemiacetalate
(2-isopropoxyoxepan-2-olate) ligand and then produced intermediate III (Figure S18). This
additional reaction can start from intermediate I or II. From I, the CL is drawn close to the titanium
center to generate a Ti-O-C-O four membered ring transition structure (TS1; Figure 6, left). In this
transition structure, the Ti-Ocarb bond length was 2.282 Å, which was longer than that of Ti-OPr
(1.978 Å) in the ring. Moreover, the Ocarb-Ccarb bond length was 1.270 Å, which was slightly longer
than that of the C=O bond of free CL (1.208 Å) but considerably shorter than the C-O single bond,
which indicated that it still has high double-bond characteristics. The OPr-Ccarb bond (1.781 Å) was
longer than that of OPr-Chemi (1.417 Å) of intermediate III. Thus, TS1 has a structure that resembles
11

intermediate I. The free energy of this transition structure was 43.1 kcal mol-1 and the activation
energy of the addition reaction from intermediate I to III was 24.9 kcal mol-1. This relatively high
activation energy can explain why this catalytic ROP progressed smoothly when the temperature
was higher than 60 oC.
OPr
TS2
TS1
Oring
Ccarb (Chemi
Ocarb
Ccarb (Chemi
Ocarbonyl
)
)
Oring
OPr
Ti
Ti
Figure 6. The ball and stick models of TS1 and TS2.
Direct transformation from II into III did not occur in our DFT calculation. When the distance
between CL and isopropyl oxide was shortened to initiate the addition reaction, the octahedral
structure of the catalyst became unstable and one equatorial isopropyl oxide was forced back to the
axial position to reform intermediate I and no stable and achievable transition structure was possible
between intermediates II and III.
After forming intermediate III, the hemiacetalate ligand rotated to draw Oring close to central Ti to
dissociating Oring from Chemi (Figure 6, right). The complex then underwent the second transition
state (TS2) to open the seven-membered CL ring. In TS2, the Oring-Ti and Ocarb-Ti bond length were
2.006 and 2.188 Å, respectively. The bond lengths of Oring-Ccarb and OPr-Ccarb were 1.737 and 1.295
Å, respectively. Thus, the transition structure had considerably higher ester characteristics than
hemiacetalate did. The free energy of TS2 was 38.4 kcal mol-1, and the activation energy of the ring
opening was 12.2 kcal mol-1 from III to IV, which was considerably lower than that of TS1 (Figure
8). This indicated that the rate determining step of this catalytic reaction was the alkyl oxide
12

addition reaction through TS1.
After ring opening, the complex formed intermediate IV with the new ester group weakly bonded to
the open pocket of CL (Figure S19). The free energy of IV was 7.7 kcal mol-1, slightly higher than
the sum of those of HLPhTiOPr2 and CL because separated molecules have greater freedom.
Although its free energy was slightly higher than that of the starting materials, the activation energy
of the reverse reaction from IV to III (30.7 kcal mol-1) was higher than the forward reaction from I
to III (23.9 kcal mol-1). Thus, its recyclization reaction was slower than ring opening. Moreover, the
considerably higher concentration of monomers compared with polymers drove the forward
reaction. Finally, the ester group was dissociated from the open pocket for binding monomers to
form intermediate V (Figure S20). Although the ester group has an almost identical structure with
intermediate VI, the chain of the polymer in the ester group was not folded on the surface of the
catalyst to cover the active site; rather, it was released in the open space. The free energy of V was
9.9 kcal mol-1, which was only slightly higher than that of VI and indicated that this conformation
change progressed smoothly. After the monomer pocket was opened, the catalytic cycle restarted
through the acceptance of another CL molecule.
13

Figure 7. Reaction mechanism of the polymerization reaction catalyzed by HLPhTiOPr2.
50
TS1
TS2
40
II
30
III
20
I
10
V
IV
0
Cat + CL
-10
Cat
.
I/II
.
TS1
.
III
.
TS2
.
IV/V
.
VI
.
Reaction Coordinate
Figure 8. Energy diagram of all intermediates and transition structures.
According to our DFT study, the most influential step of the reaction rate is that from intermediate I
to III through TS1. This can explain the reactivity difference between the three catalysts,
HLMeTiOPr2, HLPhTiOPr2, and MeLPhTiOPr2 because the higher activity of HLMeTiOPr2 compared
with HLPhTiOPr2 was attributed to the less bulky HLMe. This resulted in a larger open pocket site for
the monomer, which facilitated the monomer approach to the axial OPr ligand. This reduced the
activation energy of the addition reaction and increased the reaction rate. Because of the substituted
group difference between these two ligands, we cannot completely exclude the possibility of other
reaction mechanisms for HLMeTiOPr2 to reduce its activation energy for the catalytic reaction. The
reactivity of MeLPhTiOPr2 was higher than HLMeTiOPr2 because of the electron-donating effect of
the 4-methyl group on the pyridine ring. Favorable electron-donating ligands in Ti (IV) complexes
can reduce the strength of the bond trans to them and increase their bond length.[50] Therefore, the
Ti-OPr bond trans to the pyridine ligand in MeLPhTiOPr2 becomes weaker, and the activation energy
of TS1 state can be reduced efficiently. This explanation is also proved by our DFT calculation
results. The energy barrier of TS1 for MeLPhTiOPr2 is 0.12 cal mol-1 lower than that of HLMeTiOPr2.
14

Moreover, in the first transition structures, the Ti-O bond trans to pyridine of MeLPhTiOPr2 (1.981
Å) is slightly longer than that of HLMeTiOPr2 (1.978 Å).
3.0. Conclusions
In this study, a series of 2,6-bis(o-hydroxyalkyl)pyridine ligands and associated titanium
complexes were synthesized and used as catalysts for the ROP of CL and LA. The Ti complexes
with electron-withdrawing groups in pyridine ring or steric bulky groups in hydroxymethyl groups
reduced the catalytic activity in CL and LA polymerizations, and MeLPh-TiOPr2 exhibited the
highest catalytic activity. The mechanism of CL polymerization by the DFT calculation results
revealed that CL first formed a weak hydrogen bond with the ligand, and then approached the Ti
center. After being attacked by isopropyl oxide, the carbonyl group of CL coordinated to the Ti
center. After the rearrangement and ring opening of CL ring, CL was converted to
poly-ε-caprolactone.
Experimental Section
General
Standard Schlenk techniques and a N2-filled glove box were used throughout the isolation and
handling of all the compounds. Solvents, L-lactide, and deuterated solvents were purified prior to
use. 2,6-Dimethylpyridine, 2,4,6-trimethylpyridine, acetone, benzophenone,
N,N,N’,N’,-tertamethylethylenediamine, n-butyllithium, and titanium (IV) isopropoxide was
purchased from Sigma-Aldrich. 1H and 13C NMR spectra were recorded on a Varian
Gemini2000-200 (200 MHz for 1H and 50 MHz for 13C) spectrometer with chemical shifts given in
ppm from the internal TMS or center line of CDCl3. Microanalyses were performed using a Heraeus
CHN-O-RAPID instrument. GPC measurements were performed on a Jasco PU-2080 PLUS HPLC
pump system equipped with a differential Jasco RI-2031 PLUS refractive index detector using THF
15

(HPLC grade) as an eluent (flow rate 1.0 mL/min, at 40 °C). The chromatographic column was
JORDI Gel DVB 103 Å, and the calibration curve was made by primary polystyrene standards to
calculate MnGPC. HLMe-H30 were prepared following literature procedures.
X-ray Crystallographic Studies. Single crystals of complexes HLPh-TiOPr2 and (HLMe-TiO)4 were
obtained from a saturated dichloromethane solution in NMR tube. Suitable crystals were immersed
in FOMBLINY under a N2 atmosphere and mounted on an Oxford Xcalibur Sapphire-3 CCD
Gemini diffractometer employing graphitemonochromated Mo Kα radiation (λ = 0.710 73 Å), and
the intensity data were collected with ω scans.
General Procedures for the Polymerization of LA and CL. A typical polymerization procedure
was exemplified by the synthesis of entry 1 (Table 1) using complex HLMe-TiOPr2 as an initiator.
The polymerization conversion was analyzed by1H NMR spectroscopic studies. The 5 mL of
toluene was added to a mixture of CL (0.285 g, 2.5 mmol) and complex HLMe-TiOPr2 (0.2 mmol).
After the solution was mixed and then stirred for 11 h at 60 °C, the reaction was then quenched by
adding a drop of ethanol; the polymer was precipitated by pouring the solution into n-hexane (30.0
mL) to give white solids. The oil was dissolved in CH2Cl2 (200 mL) and the solution was washed
with water (200 mL) and the solvent removed at reduced pressure to give the white powders. Yield:
0.55 g (76%)
Synthesis of 2,2'-(pyridine-2,6-diyl)bis(1,1-diphenylethan-1-ol) (HLPh-H).
HLPh-H were prepared following literature procedures.13a To a solution of 2,6-dimethylpyridine
(2.14 g, 20 mmol) in tetrahydrofuran (25 mL, THF), n-butyllithium (2.5 M hexane solution, 20
mmol) was added dropwise at -78 oC over 1 h. Benzophenone (3.64 g, 20 mmol) in THF (20 mL)
was added. The mixture was warmed up to room temperature and stirred overnight. Then the
16

solution was again cooled at -78 oC, and additional n-butyllithium (20 mmol) was added dropwise.
The solution was warmed up to room temperature with stirring over 4 h. Then an additional
benzophenone (3.64 g, 20 mmol in THF 20 mL) was added, and the mixture was stirred overnight.
Hydrochloride acid (1 N) was added, and the mixture was stirred for 1 h, and then neutralized with
aqueous sodium carbonate, extracted twice with dichloromethane. Organic layers were washed with
water, and dried over magnesium sulfate and filtered. Volatile materials were removed under
vacuum to give yellow solid. Yield: 8.39 g (89%). 1H NMR (CDCl3, 200 MHz): δ 7.36-7.15 (m,
21H , Ar-H), 6.65 (d, J = 6.0 Hz, 2H, m-Py-H), 5.24 (br, 2H, OH), 3.64 (s, 4H, Py(CH2Ph2OH)2).
13C NMR (CDCl3, 50 MHz): δ 157.45, 146.60, 136.91, 127.95, 126.61, 126.12, 122.85 (Ar-C),
78.15 (Ph2COH), 48.13 (Ph2CCH2Py). Elemental anal. calcd for C33H29NO2(471.6): C, 84.05; H,
6.20; N, 2.97%. Found: C, 84.16; H, 6.38; N, 2.85%. Mp: 106 oC.
Synthesis of 2,2'-(4-methylpyridine-2,6-diyl)bis(1,1-diphenylethan-1-ol) (MeLPh-H).
Using a method similar to that for HLPh-H expect 2,4,6-trimethylpyridine was used in place of
2,6-dimethylpyridine. Yield: 7.96 g (82%). 1H NMR (CDCl3, 200 MHz): δ 7.36-7.15 (m, 21H ,
Ar-H), 6.48 (s, 2H, m-Py-H), 5.33 (br, 2H, OH), 3.59 (s, 4H, Py(CH2Ph2OH)2) 2.02 (s, 3H,
4-CH3-Py). 13C NMR (CDCl3, 50 MHz): δ 157.05, 148.30, 146.68, 127.90, 126.54, 126.11, 123.87
(Ar-C), 78.07 (Ph2COH), 47.87 (Ph2CCH2Py), 20.73 (4-CH3-Py). Elemental anal. calcd for
C34H31NO2(485.6): C, 84.09; H, 6.43; N, 2.88%. Found: C, 84.15; H, 6.51; N, 2.77%. Mp: 110 oC.
Synthesis of 2,6-bis(2-hydroxy-2-methylpropyl)pyridine 1-oxide (HLMeO-H).
To a solution of, was added dropwise at room temperature. A mixture of HLPh-H (2.23g, 10 mmol)
and H2O2 (10 mL) in acetic acid (50 mL) was stirred and heated at 100 oC over a week. And then
the solution was warmed up to room temperature, neutralized with aqueous sodium hydroxide, and
extracted twice with dichloromethane. Organic layers were washed with water, and dried over
magnesium sulfate and filtered. Volatile materials were removed under vacuum to give brown oil.
17

Yield: 1.31 g (55%). 1H NMR (CDCl3, 200 MHz): δ 7.39 (t, J = 8.0 Hz, 1H, p-Py-H), 7.25 (d, J =
8.0 Hz, 2H , m-Py-H), 6.45 (br, 2H, OH), 3.25 (s, 4H, Py(CH2Me2OH)2), 1.28 (s, 12H,
Py(CH2(CH3)2OH)2). 13C NMR (CDCl3, 50 MHz): δ 150.19, 128.41, 126.84, (Ar-C), 71.91
(Me2COH), 44.79 (Me2CCH2Py), 29.79 ((CH3)2CCH2Py). Elemental anal. calcd for
C13H21NO3(293.3): C, 65.25; H, 8.85; N, 5.85%. Found: C, 65.16; H, 8.68; N, 5.51%.
Synthesis of HLMe-TiOPr2
A mixture of HLMe-H (2.23 g, 10 mmol) and Ti(OPr)4 (2.84 g,10 mmol) in THF (20 mL) was stirred
for one day. Volatile materials were removed under vacuum to give yellow powder and then it was
washed with hexane (30 mL) and white powder was obtained. Yield: 2.51 g (64%).
1H NMR (CDCl3, 200 MHz): δ 7.64 (t, J = 8.0 Hz, 1H, p-Py-H), 7.05 (d, J = 8.0 Hz, 2H , m-Py-H),
4.65 (m, 2H, OCH(CH3)2), 3.07 (s, 4H, Py(CH2C(CH3)2), 1.20-1.14 (m, 24H, Py(CH2C(CH3)2,
OCH(CH3)2). 13C NMR(CDCl3, 50 MHz): δ 158.08, 137.69, 123.15, 78.83 (Py(CH2C(CH3)2), 75.73
(Py(CH2C(CH3)2), 51.59 (OCH(CH3)2), 30.03 (Py(H2C(CCH3)2), 25.97 (OCH(CH3)2). Elemental
anal. calcd for (C19H33NO4Ti): C, 58.92; H, 8.59, N, 3.62%. Found: C, 59.01; H, 8.68, N, 3.33%.
Mp: 180 oC.
Synthesis of HLPh-TiOPr2
Using a method similar to that for HLMe-TiOPr2 expect HLPh-H was used in place of HLMe-H. Yield:
5.48 g (86%). 1H NMR (CDCl3, 200 MHz): δ 7.45-7.41, 7.25-7.02 (m, 21H , Ar-H), 6.76 (d, J = 8.0
Hz, 2H, m-Py-H), 4.85 (sept, J = 6.0 Hz, 2H, OCH(CH3)2), 3.80 (s, 4H, Py(CH2Ph2O)2), 1.20 (d, J =
6.0 Hz, 12H, OCH(CH3)2). 13C NMR(CDCl3, 50 MHz): δ 156.52, 146.18, 137.21, 127.61, 127.39,
126.04, 123.74, 84.97 (Py(CH2CPh2), 77.63 (Py(CH2CPh2), 50.20 (OCH(CH3)2), 25.62
(OCH(CH3)2). Elemental anal. calcd for (C39H41NO4Ti): C, 73.70; H, 6.50, N, 2.20%. Found: C,
74.17; H, 6.90, N, 2.56%. Mp: 242 oC.
18

Synthesis of MeLPh-TiOPr2
Using a method similar to that for HLMe-TiOPr2 expect MeLPh-H was used in place of HLMe-H.
Yield: 4.38 g (67%). 1H NMR (CDCl3, 200 MHz): δ 7.42 (s, J = 8.0 Hz, 8H, Ar-H), 7.20-7.08 (m,
12H , Ar-H), 6.60 (s, 2H, m-Py-H), 4.83 (sept, J = 6.0 Hz, 2H, OCH(CH3)2), 3.73 (s, 4H,
Py(CH2Ph2O)2), 2.07 (s, 3H, 4-CH3-Py), 1.19 (d, J = 6.0 Hz, 12H, OCH(CH3)2). 13C NMR(CDCl3,
50 MHz): δ 156.09, 148.78, 147.86, 127.63, 126.06, 124.91, 120.36, 84.73 (Py(CH2CPh2), 77.22
(Py(CH2CPh2), 50.50 (OCH(CH3)2), 26.10 (OCH(CH3)2), 20.73 (PyCH3). Elemental anal. calcd for
(C40H43NO4Ti): C, 73.95; H, 6.67, N, 2.16%. Found: C, 73.64; H, 6.69, N, 1.96%. Mp: 254 oC.
Synthesis of (HLMeTi-O)4
A mixture of HLMeO-H (2.39 g, 10 mmol) and Ti(OPr)4 (2.84 g,10 mmol) in THF (20 mL) was
stirred for one day. Volatile materials were removed under vacuum to give yellow powder, and then
it was washed with hexane (30 mL), and white powder was obtained. Yield: 1.63 g (57%).
1H NMR (CDCl3, 200 MHz): δ 7.50 (t, J = 8.0 Hz, 1H, p-Py-H), 7.18 (d, J = 8.0 Hz, 2H , m-Py-H),
4.33 (d, J = 12.0 Hz, 2H, Py(CH2Me2O)2), 2.52 (d, J = 12.0 Hz, 2H, Py(CH2Me2O)2), 1.47 (s, 6H,
Py(CH2(CH3)2O)2), 0.77 (s, 6H, Py(CH2(CH3)2O)2). 13C NMR (CDCl3, 50 MHz): δ 152.22, 132.17,
125.30 (Ar-C), 79.50, 78.43 (Me2CO), 44.15, 32.18 (Me2CCH2Py), 28.57, 24.73 ((CH3)2CCH2Py).
Elemental anal. calcd for (C52H76N4O12Ti4): C, 54.76; H, 6.72, N, 4.91%. Found: C, 54.54; H, 6.31,
N, 4.58%. Mp: 268 oC.
Synthesis of HLMe2-Ti
A mixture of HLMe-H (4.46 g, 20 mmol) and Ti(OPr)4 (2.84 g,10 mmol) in THF (20 mL) was stirred
at 40 oC for one day. Volatile materials were removed under vacuum to give white powder, and then
it was washed with hexane (50 mL), and white powder was obtained. Yield: 3.23 g (66%).
1H NMR (CDCl3, 200 MHz): δ 7.55 (t, J = 8.0 Hz, 1H, p-Py-H), 6.98 (d, J = 8.0 Hz, 2H , m-Py-H),
3.26 (br, 4H, Py(CH2Me2O)2), 1.42-1.10 (m, 12H, Py(CH2(CH3)2O)2). 13C NMR (CDCl3, 50 MHz):
19

δ 157.94, 137.20, 122.71 (Ar-C), 77.63 (Me2CO), 51.58 (Me2CCH2Py), 30.43 ((CH3)2CCH2Py).
Elemental anal. calcd for (C26H38N2O4Ti): C, 63.67; H, 7.81, N, 5.71%. Found: C, 63.36; H, 7.91, N,
5.87%. Mp: 202 oC.
DFT calculation. The DFT calculation was carried out using the Gaussian09 program. The
structures were built according to the crystal structure of HLPhTiOPr2. Its geometry optimization was
carried out using B3LPY.[51] The LanL2DZ basis set[52, 53] was used for Ti atom, and the
6-31G(d) basis set[54] was for other atoms. The temperature for the calculation was set to 333.15 K.
The polarizable continuum model was used for simulate the solvent effect of toluene.[55] The
minimum energy stationary points of intermediates and the saddle points of transition states were
confirmed by frequency analysis with the same calculation level.
AUTHOR INFORMATION
Corresponding Author
*E-mail for H.-Y.Chen: hchen@kmu.edu.tw
C.-C. Chiu: cchiu@kmu.edu.tw
K.-H. Wu: wukuohui@chem.s.u.-tokyo.ac.jp
ORCID: 0000-0003-1424-3540
Notes
The authors declare no competing financial interest.
Author Contributions
‡These authors contributed equally
Acknowledgments
This study is supported by Kaohsiung Medical University (#NSYSUKMU 107-P010 and KMU-
DK109004), and the Ministry of Science and Technology (Grant MOST 107-2113-M-037-001 and
108-2314-B-037-051). We thank Center for Research Resources and Development at Kaohsiung
Medical University for the instrumentation and equipment support.
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24

Highlights
Ti compounds bearing 2,6-bis(o-hydroxyalkyl)pyridine ligands were synthesized.
LA and CL polymerizations were investigated.
MeLPh-TiOPr2 exhibited the highest catalytic activity.

Declaration of interests
■ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: