Mechanism of living lactide polymerization by dinuclear indium catalysts and its impact on isoselectivity

Article abstract of DOI:10.1021/ja3048046

A family of racemic and enantiopure indium complexes 1-11 bearing bulky chiral diaminoaryloxy ligands, H(NNO_R), were synthesized and fully characterized. Investigation of both the mono- and the bis-alkoxy-bridged complexes [(NNO_R)InX]₂[μ-Y][μ-OEt] (5, R = ^tBu, X = Y = Cl; 8, R = Me, X = I, Y = OEt) by variable temperature, 2D NOESY, and PGSE NMR spectroscopy confirmed dinuclear structures in solution analogous to those obtained by single-crystal X-ray crystallography. The dinuclear complexes in the family were highly active catalysts for the ring-opening polymerization (ROP) of lactide (LA) to form poly(lactic acid) (PLA) at room temperature. In particular, complex 5 showed living polymerization behavior over a large molecular weight range. A detailed investigation of catalyst stereoselectivity showed that, although (R,R/R,R)-5 is highly selective for l-LA, only atactic PLA is obtained in the polymerization of racemic LA. No such selectivity was observed for complex 8. Importantly, the selectivities obtained for the ROP of racemic LA with (R,R/R,R)-5 and (R,R/R,R)-8 are different and, along with kinetics investigations, suggest a dinuclear propagating species for these complexes.

Full text of DOI:10.1021/ja3048046

Article
pubs.acs.org/JACS
Mechanism of Living Lactide Polymerization by Dinuclear Indium
Catalysts and Its Impact on Isoselectivity
Insun Yu, Alberto Acosta-Ramírez, and Parisa Mehrkhodavandi*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
S
* Supporting Information
ABSTRACT: A family of racemic and enantiopure indium
complexes 1−11 bearing bulky chiral diaminoaryloxy ligands,
H(NNOR), were synthesized and fully characterized. Inves-
tigation of both the mono- and the bis-alkoxy-bridged
t
complexes [(NNOR)InX]2[μ-Y][μ-OEt] (5, R = Bu, X = Y
= Cl; 8, R = Me, X = I, Y = OEt) by variable temperature, 2D
NOESY, and PGSE NMR spectroscopy confirmed dinuclear
structures in solution analogous to those obtained by single-
crystal X-ray crystallography. The dinuclear complexes in the
family were highly active catalysts for the ring-opening
polymerization (ROP) of lactide (LA) to form poly(lactic acid) (PLA) at room temperature. In particular, complex 5 showed
living polymerization behavior over a large molecular weight range. A detailed investigation of catalyst stereoselectivity showed
that, although (R,R/R,R)-5 is highly selective for L-LA, only atactic PLA is obtained in the polymerization of racemic LA. No such
selectivity was observed for complex 8. Importantly, the selectivities obtained for the ROP of racemic LA with (R,R/R,R)-5 and
(R,R/R,R)-8 are different and, along with kinetics investigations, suggest a dinuclear propagating species for these complexes.
of multiple metal centers in lactide ROP (Scheme 1). One
possibility is a catalyst that is dinuclear in the solid state but is
mononuclear in solution, as in the case of diaminophenolate
zinc alkoxide (A).24 In this case, the plot of −d[LA]/dt is
proportional to [A/2]n with n = 1.33 (0 °C) or 1.75 (25 °C)
indicating a possible fractional dependence on catalyst,
although plots of kobs versus [A/2]o are linear. The dinuclear
BDI zinc alkoxide (B) complex also exhibits a fractional order
in catalyst: −d[LA]/dt = kp[Zn]1.56[LA].25 A catalyst that is
mononuclear in solution as well as in the solid state, such as
iron alkoxide catalyst (C), can also exhibit fractional order in
catalyst.22 This fractional dependence is interpreted by using a
model of active chain aggregation.29 In contrast, the scandium
complexes bearing 1,ω-dithioalkanediyl-bridged bisphenolato
(OSSO)-type ligands (D) are dinuclear in solution as well as in
the solid state.28 A slow dissociation of this dimer to an active
lactide adduct D/2·lactide similar to those obtained in
analogous yttrium complexes was proposed.30 Phosphine
oxide-bridged dinuclear yttrium amido complexes (E) remain
dinuclear in solution as well as in the solid state; however, they
can change from a single to a double site catalyst based on the
steric bulk of the amido initiator.27 Finally, the dizinc−
monoalkoxide complex supported by a dinucleating ligand
(F) is first order in the dinuclear catalyst and does not show
significant aggregation phenomena.26 From the above sample
studies, it is clear that significant work is necessary to shed light
INTRODUCTION
■
Biodegradable polyesters such as poly(lactic acid) (PLA)1 have
been of intense interest for the past two decades because of
their environmental advantages in applications ranging from
packaging and agricultural materials to drug delivery and
medical devices.2 In recent years, the ring-opening polymer-
ization (ROP) of cyclic esters such as lactide (LA) catalyzed by
organocatalysts,3 as well as discrete metal complexes bearing
various ligand architectures,4 has been heavily explored in an
attempt to control polymer micro- and macrostructures and
limit transesterification or other uncontrolled chain transfer
events.5 In particular, there has been a strong focus on Lewis
acidic centers such as alkali metals,6 alkaline earth metals, and
Zn,7 Al,8,9 Ga,10 Ge,11 Sn,12 Bi,13 Fe,14 other transition metals,15
as well as rare earth metals.16
We are interested in developing catalysts for the controlled
ROP of racemic LA (rac-LA) and have reported the first
example of an indium complex used as an initiator for the living
polymerization rac-LA17 to form PLAs with moderate isotactic
enrichment and low polydispersity indices (PDIs).18 We have
reported on some properties and applications of these catalysts
and the resulting polymers.19 Following our contributions,
other research groups have reported the synthesis of indium
complexes supported by both chiral and achiral20 ligands, as
well as simple In(III) salts21 that were used as lactide
polymerization initiators. A number of these indium catalysts
are dinuclear20b−d or are postulated to have multinuclear active
centers based on model initiators.21
Early reports of catalysts bearing iron,22,23 zinc,24−26 and rare
earth metals27,28 demonstrate a range of possibilities for the role
Received: May 17, 2012
Published: July 5, 2012
© 2012 American Chemical Society
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Scheme 1. Some Catalysts for the ROP of Lactide
Scheme 2. Two Mechanistic Proposals for ROP of LA by [(NNOtBu)InCl]2(μ-Cl)(μ-OEt)
on the subtle mechanistic aspects of polymerization by Lewis
acid catalysts capable of aggregation.
provide a more nuanced picture of the various processes
involved.
In our initial communication,17 we reported that an ethoxy-
chloro-bridged dinuclear indium complex, [(NNOtBu)InCl]2(μ-
Cl)(μ-OEt), catalyzed the living polymerization of up to 500
equiv of LA following an induction period. We proposed a
mechanism similar to that reported for the scandium catalyst D,
above,28,30 involving the dissociation of the dinuclear complex
to yield an active mononucler propagating species (NNOtBu)-
In(Cl)(OEt) and an inactive complex (NNOtBu)InCl2 (Scheme
2A).
In this work, we present our full investigation into the
polymerization of rac-LA by this family of dinuclear alkoxy-
bridged catalysts and rule out the dissociative mechanism. Our
investigations strongly indicate that the propagating species is
dinuclear. We propose an alternative mechanism, involving two
metal centers that can stabilize the propagating polymer chain
(Scheme 2B), which explains the highly living character of the
catalyst. Extensive studies of the stereoselectivity of the catalyst
for the ROP of rac-, L-, and D-LA support this mechanism and
RESULTS
■
Synthesis and Characterization of Racemic Alkoxy-
Bridged Indium Complexes. Racemic 2-t-butyl-4-R-6-(((2-
(dimethylamino)cyclohexyl)amino)methyl)phenol proligands
( )-H(NNOR), where R is a para methyl or t-butyl substituent
on the phenol, were synthesized according to previously
reported methods (see the Supporting Information).17,31
Dihalide indium complexes bearing these ligands, (NNOtBu)-
InX2 (1, X = Cl; 2, X = I) and (NNOMe)InX2 (3, X = Cl; 4, X =
I), were prepared by addition of the potassium salts of the
proligands, K(NNOR), to the appropriate indium trihalide
(Scheme 3, see the Supporting Information for the solid-state
structure of ( )-3).19a Addition of 2 equiv of NaOEt to
complexes 1−4 formed monoalkoxy-bridged dinuclear com-
plexes [(NNOtBu)InCl]2(μ-Cl)(μ-OEt) (5) and [(NNOMe)-
InX]2(μ-X)(μ-OEt) (X = Cl (6), I (7)). The NMR spectra
(CD2Cl2) of 6 and 7 prepared from rac-H(NNOMe) show
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Scheme 3. Synthesis of Dinuclear Indium Complexes of the Type [(NNOR)InX]2(μ-Y)(μ-OEt) (1, 2, and 5 Have Been
Reported)17,19a
Scheme 4. Synthesis of Hydroxy-Bridged Complexes [(NNOR)InI]2(μ-OH)(μ-OEt)
signals corresponding to one compound, as did the previously
reported [(NNOtBu)InCl]2(μ-Cl)(μ-OEt) (5) (Figures S5−
S8). The solid-state structure of ( )-5 shows a homochiral
dimer with (R,R/R,R) centers, implying that the (S,S/S,S)
enantiomer also exists in solution.17
Addition of 4 to a suspension of a 2-fold excess of NaOEt in
toluene forms a mixture of 7 and a bis-ethoxy-bridged complex,
[(NNOMe)InI(μ-OEt)]2 (8), respectively (Scheme 3).32 The
analogous, highly insoluble complex with a para-t-Bu group,
[(NNOtBu)InI(μ-OEt)]2 (9), is synthesized in a similar manner.
Upon addition of 1 equiv of water, the bis ethoxy-bridged
complexes 8 and 9 convert to the hydroxy-ethoxy dinuclear
complexes [(NNOR)InI]2(μ-OH)(μ-OEt) (R = Me (10), t-Bu
Figure 1. Molecular structure of meso-9 (depicted with ellipsoids at
1
(11)) (Scheme 4). The H NMR spectra (CD2Cl2) of 10 and
11 are similar to the spectra obtained for asymmetrically
bridged complexes 5, 6, and 7 (Figures S15−18).
50% probability and H atoms omitted for clarity). Selected bond
lengths (Å): In1−I1 2.8068(3), In1−O1 2.082(2), In1−O2 2.163(2),
In1−N1 2.275(2), In1−N2 2.381(3). Selected bond angles (deg):
O1−In1−O2i 91.22(8), O1−In1−O2 163.88(8), O1−In1−I1
92.77(6), O1−In1−N1 85.06(8), O1−In1−N2 94.93(9), N1−In1−
N2 75.97(9), N2−In1−O2 98.69(9), Ni−In1−I1 171.11(6), In1−
O2−In1i 105.84(8).
The molecular structure of 9, which was synthesized from
rac-H(NNOtBu), shows a heterochiral dimer (meso-9) with
(R,R/S,S) configuration (Figure 1). In contrast, the solid-state
structure of 11, synthesized from rac-H(NNOtBu), shows a
homochiral dimer with (R,R/R,R) configuration, implying that
the (S,S/S,S) analogue of ( )-11 exists in solution (Figure 2).
Complexes 5 and 11 have similar In−N bond distances, and
there is a “cis” relationship between the phenoxy moieties of
the ligand (the phenoxy groups are on the same hemisphere of
the molecule). Addition of excess water to these complexes
forms the previously described hydroxy-bridged complexes
[(NNOR)InX(μ-OH)]2.19a
Synthesis and Characterization of Enantiopure
Alkoxy-Bridged Indium Complexes. (R,R)- and (S,S)-
H(NNOR), where R is a para-methyl or t-butyl substituent on
the phenol group, were synthesized in a manner analogous to
that of ( )-H(NNOR) (see the Supporting Information),17,31
as were the dihalide complexes (NNOtBu)InX2 ((R,R)- and
(S,S)-1: X = Cl) and (NNOMe)InX2 ((R,R)- and (S,S)-4: X =
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and O−CH2CH3, as would be expected from a centrosym-
metric complex (Figure 3b).
The molecular structure of (S,S/S,S)-8, obtained by single-
crystal X-ray diffraction, shows two homochiral octahedral
indium centers with no center of symmetry in the molecule
(Figure 4). This is in contrast to the structure of meso-9 (Figure
Figure 2. Molecular structure of ( )-11 (depicted with ellipsoids at
50% probability and H atoms as well as solvent molecules omitted for
clarity). Selected bond lengths (Å): In1−O1 2.180(3), In2−O1
2.211(3), In1−O2 2.142(3), In2−O2 2.146(3), In1−O3 2.090(3),
In1−N3 2.336(4), In1−N4 2.273(4), In1−I2 2.8030(4), In2−I1
2.7923(4), In2−O4 2.099(5), In2−N1 2.338(9), In2−N2 2.265(5).
Selected bond angles (deg): O1−In1−O2 92.49(12), N3−In1−I2
96.20(10), N3−In1−O3 103.29(14), N1−In2−I1 98.20(15), N1−
In2−O4 100.14(5), O1−In2−O2 74.58(12), In1−O1−In2
103.26(13), In1−O2−In2 106.90(14), O2−In1−O3 165.62(12).
Figure 4. Molecular structure of (S,S/S,S)-8 (depicted with ellipsoids
at 50% probability and H atoms omitted for clarity). Selected bond
lengths (Å): In1−O1 2.101(4), In2−O2 2.100(4), In1−O3 2.187(4),
In2−O3 2.174(3), In1−O4 2.176(3), In2−O4 2.174(4), In1−N1
2.270(5), In1−N2 2.387(5), In2−N3 2.259(5), In2−I4 2.379(4),
In1−I1 2.8052(5), In2−I2 2.7980(5). Selected bond angles (deg):
O1−In1−O4 162.29(15), O1−In1−O3 87.89(14), O4−In1−O3
75.07(11), O1−In1−N1 85.27(16), O4−In1−N1 92.39(16), O3−
In1−N1 98.38(17), O1−In1−N2 98.69(14), O4−In1−N2 97.80(14),
O3−In1−N2 171.12(15), N1−In1−N2 76.36(18), O1−In1−I1
92.23(12), O4−In1−I1 93.22(12), O3−In1−I1 92.35(11), N1−
In1−I1 168.87(12), N2−In1−I1 93.35(13), O2−In2−O4 88.28(14),
O2−In2−O3 163.08(14), O4−In2−O3 75.38(11), O2−In2−N3
89.10(16), O4−In2−N3 95.78(16), O3−In2−N3 88.24(15), O2−
In2−N4 92.31(14), O4−In2−N4 172.58(17) O3−In2−N4
103.33(14), N3−In2−N4 76.84(16), O2−In2−I2 93.25(12), O4−
In2−I2 92.14(12), O3−In2−I2 91.74(11), N3−In2−I2 171.81(11),
N4−In2−I2 95.22(12).
I). The NMR spectra of the enantiomers are identical to those
of the racemic complexes (see the Supporting Information).
The solid-state structure of (S,S)-4 shows a distorted trigonal
bipyramid with the iodo ligands in the axial and equatorial
positions, while in ( )-3 both chloro ligands are in the
equatorial position (Figures S22 and S23).
Enantiopure mono- and bis-ethoxy-bridged complexes (R,R-,
S,S-5) and (R,R-, S,S-8) were synthesized in a manner
analogous to that of their racemic counterparts. The 1H
NMR spectra of complex 5 generated from ( )-, (R,R)-, and
(S,S)-H(NNOtBu) are identical, suggesting that the species
observed in solution for ( )-5 are indeed the two homochiral
enantiomers (R,R/R,R)- and (S,S/S,S)-5 (Figure 3a). In
1
contrast, while the H NMR spectra of (R,R/R,R)- and (S,S/
S,S)-8 are identical, the 1H NMR spectrum of meso-8 is
different and shows only two signals for each of Ar−CH2−N
1) that shows a centrosymmetric heterochiral dimer. meso-8 is
the thermodynamically favored form of the complex: a 1:1
mixture of (R,R/R,R)- and (S,S/S,S)-8 converts to (R,R/S,S)-8
in a few hours at room temperature (Figure S21). Reaction of
(R,R/R,R)-8 with adventitious water forms the nearly
isostructural bis-hydroxy-bridged complex (R,R/R,R)-
[(NNOMe)In(I)(μ-OH)]2 (Figure S24). Again, this is in
contrast to the bis-hydroxy-bridged dimers in this series,
which have been isolated in the centrosymmetric meso-
forms.17,19a
Dinuclear Nature of Ethoxy-Bridged Complexes in
Solution. All alkoxy-containing complexes in this family have a
dinuclear structure in the solid state, and we show above that
the solution structures of (S,S/S,S)- and (R,R/S,S)-8 reflect the
differences observed in the analogous solid-state structures.
Additional data, below, support the dinuclear nature of the
alkoxy-bridged complexes in solution.
1
(1) Variable-temperature H NMR spectra of 5 and 8 show
no changes over a wide temperature range (Figures S25
and S26).
(2) NOE experiments with 5 and 8 support dinuclear
1
structures. The H NOESY-2D NMR spectrum of 5
shows through-space interactions between In−
OCH2CH3 and the phenolate ortho-C(CH3)3 protons
only (Figure S27). Importantly, cross peaks are not
1
Figure 3. H spectra (CDCl3, 25 °C) of (a) ( )-, (R,R/R,R)-, and
(S,S/S,S)-5, and (b) (meso)-, (R,R/R,R)-, and (S,S/S,S)-8.
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Figure 5. Through-space interactions expected for mononuclear ethoxy complexes and observed in the 1H NOESY-2D NMR spectra of complexes 5
(left), and 8 and 9 (right) (CDCl3, 25 °C).
observed between In−OCH2CH3 and the protons of
N(CH3)2, indicating an asymmetric environment around
In−OCH2CH3 (Figure 5, left). There is also a clear
through-space interaction between In−OCH2CH3 and
only one of the NCH2−Ar protons of the ancillary
law (rate = k[catalyst][LA]) (Figure S35). This allows us to
directly compare k values for the four catalysts in question
(Table 1).
Table 1. Rate Constants for the ROP of rac-LA Using
1
a
ligand. In contrast, the H NOESY-2D NMR spectrum
Dinuclear Indium Initiators
of 8 (Figure 5 right) shows through-space interactions
between OCH2CH3 and the phenolate ortho-C(CH3)3 as
well as between In−OCH2CH3 and the protons of
N(CH3)2 (Figure S28). Similar cross peaks are observed
for complex 9 (Figure S29). The calculated distances
between In−OCH2CH3 and ligand protons for 5 and 8
entry
catalyst
k (M−1 s−1
)
b
1
[(NNOtBu)InCl]2(μ-OEt)(μ-Cl) (5)
[(NNOMe)InI]2(μ-OEt)(μ-I) (7)
[(NNOMe)InI(μ-OEt)]2 (8)
0.57(0.05)
1.35(0.11)
1.78(0.26)
1.50(0.13)
b
2
c
3
b
4
[(NNOMe)InI]2(μ-OEt)(μ-OH) (10)
1
a
using H NOESY-1D spectroscopy are in good agree-
All reactions were carried out in an NMR tube in CDCl3 at 25 °C and
followed by 90% conversion. [LA] = 0.91 M. [catalyst] = 0.0091 M .
[LA] = 0.228 M. [catalyst] = 0.00228 M. 1,3,5-Trimethoxybenzene
(TMB) was used as internal standard. The value of kobs was
determined from the slope of the plots of ln([LA]/[TMB]) versus
time.
b
ment with the values obtained from the solid-state
structures (Figures S30 and S31).
c
(3) Pulsed-gradient spin−echo (PGSE) NMR experiments33
are in agreement with the solid-state structures and
support dinuclear solution structures for 5 and 8. The
diffusion coefficients (Dt) of the proligand (12.0 × 10−10
m2 s−1), the mononuclear complex 1 (10.4 × 10−10 m2
s−1), and the previously reported complex (NNOtBu)In-
(CH3)2 (11.1 × 10−10 m2 s−1)19a are significantly faster
than those of 5 (7.8 × 10−10 m2 s−1) and 8 (7.9 × 10−10
m2 s−1) (Figure S32). The hydrodynamic radii (rH) of
the dinuclear species (5, 7.5 Å; 8, 7.4 Å) calculated from
the modified Stokes−Einstein equation33 are consistent
with the structurally determined values (5, 7.3 Å; 8, 6.7
Å) estimated from the X-ray crystallographic data (Table
S4).
The rate constant for the ROP of LA with 5 in CDCl3 is
comparable to the reported value in CD2Cl2.17 The rates of
propagation for the iodo analogues, 7, 8, and 10, are
significantly higher than that for 5. On the basis of our
previous studies on the role of halides in dinuclear indium
complexes,19a we believe that this increase is due to the greater
electrophilicity of the indium centers in the chloro analogues.
This enhanced electrophilicity is expected to strengthen the
initiator−LA interaction and slow ring-opening and propaga-
tion. Importantly, the monoalkoxy complexes 7 and 10 have
nearly identical rates, within error, to the bis-alkoxy-bridged
complex 8 (Table 1, entries 2−4). This would not be expected
if complex 8 dissociated to form two initiating species. The
activation parameters of the mono- and bis-ethoxy-bridged
complexes 7 (ΔH⧧ = 47(3) kJ mol−1, ΔS⧧ = −83(7) J K−1
mol−1) and 8 (ΔH⧧ = 62(4) kJ mol−1, ΔS⧧ = −30(3) J K−1
mol−1)34 are in agreement with reported values for complex 5
and other indium catalysts for LA ROP and indicate similar
ordered transition states in a coordination−insertion mecha-
nism (Figures S36, S37).17,20b
Living Ring-Opening Polymerization (ROP) of Lactide.
Dinuclear complexes 5, 7, 8, and 10 are excellent initiators for
lactide polymerization and were studied in depth. The choice of
solvent for carrying out comparative experiments was
complicated by the limited solubility of the bis-ethoxy-bridged
complex 8 in all solvents except CDCl3; the role of solvent will
be discussed further below.
The rates of LA ROP with the para-t-Bu and -Me substituted
complexes 5 and 6 are identical under the same conditions
(Figure S33). The reactions of rac-LA with catalysts 5, 6, 8, and
10 were monitored by H NMR spectroscopy at 25 °C up to
In our communication,17 we reported that the ROP of LA
with 5 was a living process, with a linear increase of Mn values
and low molecular weight distributions for monomer:initiator
(M/I) ratios up to 500. We have expanded this range to M/I
ratios of over 2100 with the same control, obtaining polymers
with molecular weights up to 350 kDa with very low PDI values
(Figure 6). These results confirm that complex 5 is one of the
most controlled catalysts reported for the ROP of LA.4,5
Although the rates of polymerization for the mono- and bis-
ethoxy-bridged complexes 7 and 8 are identical, the molecular
1
90% conversion of 200 equiv of rac-LA (∼50 min), with
variations in rate depending on the initiator and reaction
conditions. In all cases, an induction period was observed
(Figure S34).
After the initiation period, the polymerization rates are first
order in LA concentration (rate = kobs[LA]). The polymer-
ization rate is also first order in the concentration of dinuclear
complexes 5, 7, 8, and 10, indicating that there is one initiating
species for all complexes, and give an overall second-order rate
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( )-[(NNOMe)InI]2(μ-OEt)(μ-I) (7) are identical (Figure
S40g).
The rates of polymerization for enantiopure 5 reveal strong
site selectivity. Comparison of the ROP rates for D- and L-LA
with (R,R/R,R)-5 shows a kL/kD value of ∼14; the reverse value
(kD/kL ≈ 14) is obtained for (S,S/S,S)-5 (Table 3, entries 1−
Table 3. Effects of Catalyst Chirality on Reaction Rates and
a
Polymer Tacticity by Mono-ethoxy-Bridged Complex 5
b
entry
catalyst
monomer
kobs (×10−3 s−1
)
Pm
1
2
3
4
5
(R,R/R,R)-[5]
(R,R/R,R)-[5]
(S,S/S,S)-[5]
(S,S/S,S)-[5]
(R,R/R,R)-[5]
L-LA
3.4 (0.6)
1
D-LA
L-LA
0.25 (0.14)
0.27 (0.04)
3.8 (0.8)
1
1
D-LA
rac-LA
1
c
0.62 (0.16)
0.48
d
0.21 (0.06)
c
6
(S,S/S,S)-[5]
rac-LA
0.70 (0.05)
0.49
d
0.24 (0.01)
7
8
9
( )-[5]
( )-[5]
( )-[5]
L-LA
2.98 (0.09)
2.95 (0.08)
1.72 (0.16)
1
■
Figure 6. Plot of observed PLA Mn ( ) and molecular weight
D-LA
rac-LA
1
▲
distribution ( ) as functions of added rac- or L-LA for catalyst 5 (Mn
0.61
= number averaged molecular weight, PDI = polydispersity index).
The line indicates calculated Mn values based on the LA:initiator ratio.
All reactions were carried out at room temperature in CH2Cl2, and
polymer samples were obtained at >90% conversion.
a
All reactions were carried out with 200 equiv of LA in CDCl3 at 25
°C and followed to 90% conversion by 1H NMR spectroscopy, unless
b
otherwise stated. [catalyst] = 0.0023 M, [LA] = 0.45 M. Average of
two experiments. kobs from 0% to 64% conversion. kobs from 73% to
c
d
90% conversion.
weight of polymers obtained using the two catalysts depends on
the number of alkoxides in the molecule (Table 2). Polymers
obtained with the monoethoxy-bridged catalysts 5 and 7 show a
good correlation between the theoretical Mn based on dimer
concentration (Table 2, entries 1−4). In contrast, those
obtained with the bis-ethoxy-bridged complex 8 show Mn
values roughly one-half of the theoretical values, indicating
the presence of two propagation sites for 8 (Table 2, entries 5−
7). Thus, for the bis-ethoxy-bridged catalyst 8, polymer
molecular weights are indicative of one polymer chain per
ethoxide.
Control of Stereoselectivity with Dinuclear Catalysts.
We have previously communicated that ( )-5 exerts moderate
isoselectivity for the ROP of rac-LA (Pm = 0.62).17 In the
current study, we investigate the stereoselectivity of racemic
and enantiopure dinuclear complexes ( )-, (R,R/R,R)-, and
(S,S/S,S)-5 and meso-, (R,R/R,R)-, and (S,S/S,S)-8 for the
polymerization of rac-, D-, and L-LA (CDCl3, 25 °C) in depth
(Figures S38−S41). We do not observe a halide effect:
selectivities for ( )-[(NNOtBu)InCl]2(μ-OEt)(μ-Cl) (5) and
4).36 This krel value is similar to those reported for highly
selective chiral aluminum salen complexes.9 Despite this high
selectivity, and in contrast to the aluminum systems, polymer-
ization of rac-LA with enantiopure 5 forms atactic PLA (Table
3, entries 5,6). Polymerization of rac-LA with (R,R/R,R)-5
follows two rate regimes (Figure 7a). In the early stages of the
polymerization, a rate of 0.62 × 10−3 s−1 is observed; however,
after ∼30 min, there is a sharp decrease in the rate to 0.21 ×
10−3 s−1. This is the rate observed for the disfavored monomer.
Similar values are observed for (S,S/S,S)-5, indicating that the
favored monomer is polymerized first, at a faster rate, than the
disfavored (Figure S38). In contrast, the kobs values for
polymerization of L- and D-LA with ( )-5 (Table 3, entries
7,8) are identical to the analogous enantiopure complexes
within error (Table 3, entries 1,4). Importantly, the rate of
polymerization of rac-LA with ( )-5 (Table 3, entry 1) is
significantly lower than the rates for enantiopure monomers,
indicating catalyst inhibition by the mismatched monomer.
There is a nonlinear relationship between the observed rate
constant and percent (R,R/R,R)-5. As the enantiopurity of the
Table 2. Polymerization rac-LA by Complexes 5, 7, and 8
a
b
c
c
entry
initiator
[LA]o:[dimer]
solvent
conv. (%)
Mn,theo /g mol−1
Mn,GPC /g mol−1
Mw/Mn
1
2
3
4
5
6
7
5
5
7
7
8
8
8
1005
1002
510
CH2Cl2
CHCl3
93
98
95
95
92
93
95
134 760
141 580
68 880
129 800
148 400
50 050
1.04
1.04
1.17
1.12
1.16
1.14
1.26
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
976
133 680
66 350
141 700
35 940
500
1000
2001
134 090
273 960
61 490
154 900
a
b
c
Monomer conversion, determined by 1H NMR spectroscopy. Calculated from [LA]o/[initiator] × LA conversion × MLA + MEtOH. Determined
by GPC−LALLS (gel permeation chromatography−low angle laser light scattering) to the polystyrene standard calibration curve via the Mark−
Houwink equation in THF at 25 °C ([η] = KMa, while [η] = intrinsic viscosity, M = molecular weight, and K and a are Mark−Houwink parameters,
K = 1.832 × 10−4 dL/g, and a = 0.69 dn/dc = 0.042 mL/g).35 All reactions were carried out for 16 h.
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Figure 7. Plot of ln[LA] versus time for polymerization of rac-LA, L-LA, and D-LA by (a, left) (R,R/R,R)-5 and (b, right) (R,R/R,R)-8 (CDCl3, 25
°C).
◆
●
( ) and Pm ( ) as functions of catalyst enantiopurity. All reactions were carried out with 200 equiv of rac-LA in CDCl3 at 25
Figure 8. Plots of kobs
°C and followed to 90% conversion. (a, left) [5] = 0.0024 M, [LA] = 0.46 M; (b, right) [8] = 0.00057 M, [LA] = 0.117 M.
d
samples increases from ( )-5 (50%) to (R,R/R,R)-5 (100%),
the observed rate constants decrease an order of magnitude in a
nonlinear fashion, while Pm values decrease from ∼0.6 to 0.5,
again in a nonlinear fashion (Figure 8a). Such nonlinear
relationships are a characteristic of dinuclear stereoselective
catalysts.37 Pm values for ROP of rac-LA with ( )- and (R,R/
R,R)-5 remain essentially unchanged with increasing conversion
(at 25 and 0 °C), confirming that the resulting polymers are
not blocky (Figure S41).
In contrast to the monoethoxy-bridged complex 5, polymer-
izations of LA with bis-ethoxy-bridged complex 8 does not
show significant site selectivity. The kL/kD value for ROP of L-
LA with (R,R/R,R)-8 is only ∼2, with the opposite selectivity of
the same magnitude observed for (S,S/S,S)-8 (Table 4, entries
1−4). Pm values for the polymerizations of rac-LA with meso- or
enantiopure 8 are the same (Table 4, entries 5−7). The rate
constants for ROP of rac-, D-, and L-LA with meso-8 are
identical within experimental error (Table 4, entries 7−9).
Observed rate constants and Pm values do not change with
increasing enantiopurity of the catalyst (Figure 8b). These data
suggest that the observed selectivity (Pm = 0.65) with catalyst 8
is not affected by catalyst chirality and thus must be dominated
by chain end control.
On the Solution Structure of the Propagating Species
for Catalyst 5. The Pm values obtained for the ROP of rac-LA
with (R,R/R,R)-5 (0.48) and (R,R/R,R)-8 (0.65) are
significantly different. This would not be possible if the
polymers were derived from identical mononuclear initiators.
Indeed, the kinetics and selectivity data discussed above
strongly suggest a dinuclear propagating species for catalyst 5.
To probe the nature of the catalyst during polymerization
and differentiate between the mechanisms outlined in Scheme
2, we monitored the dissociation of 5 in the presence of added
donors. Complex 5 remains unchanged after 24 h after the
addition of 2 equiv of pyridine, ethyl acetate, and ethanol, as
1
observed by H NMR spectroscopy (CDCl3, 25 °C, Figure
S42). Irreversible changes are observed upon addition of a
1
larger excess of a donor (Scheme 5). Variable-temperature H
Table 4. Effects of Catalyst Chirality on Reaction Rates and
a
NMR spectra (25 to −82 °C, CD2Cl2) of a mixture of 5 and 10
equiv of pyridine show new signals for coordinated pyridine,
which can be observed below −30 °C (Figure S43). When
complex 5 is heated to 100 °C in neat pyridine for 48 h, signals
for at least two new complexes as well as pyridine are observed
in the 1H NMR spectra; however, complex 5 remains the major
species in solution (Figure S44). A 2D NOESY spectrum of
this mixture shows no correlations between the proton signals
of pyridine and 5, while correlations between pyridine and at
least one of the new byproducts are observed (Figure S45). We
have reported that in a similar reaction with [NNOtBu]InCl2
(1), the pyridine adduct forms quantitatively.17 Therefore,
dinuclear complex 5 may be dissociated in the presence of a
strong base under forcing conditions to form base-adducts;
however, the majority of the parent complex 5 remains
Polymer Tacticity by Bis-ethoxy-Bridged Complex 8
b
entry
catalyst
monomer
kobs (×10−3 s−1
)
Pm
1
2
3
4
5
6
7
8
9
(R,R/R,R)-[8]
(R,R/R,R)-[8]
(S,S/S,S)-[8]
(S,S/S,S)-[8]
(R,R/R,R)-[8]
(S,S/S,S)-[8]
(meso)-[8]
L-LA
1.25 (0.21)
0.64 (0.01)
0.67 (0.16)
1.29 (0.30)
0.72 (0.01)
0.66 (0.09)
1.73 (0.76)
1.24 (0.03)
1.23 (0.02)
1
D-LA
L-LA
1
1
D-LA
rac-LA
rac-LA
rac-LA
L-LA
1
0.65
0.64
0.62
1
(meso)-[8]
(meso)-[8]
D-LA
1
a
All reactions were carried out with 200 equiv of LA in CDCl3 at 25
°C and followed to 90% conversion by 1H NMR spectroscopy.
[catalyst] = 0.00052 M, [LA] = 0.114 M. Average of two experiments.
b
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Scheme 5. Irreversible Reactions of [(NNOtBu)InCl]2(μ-Cl)(μ-OEt) (5) with Donors
unreacted, attesting to the stability of the dinuclear structure in
solution.
The thermodynamic stability of the dinuclear complex does
not preclude reactivity. As previously reported, reaction of
( )-5 with water yields the meso form of the bis-hydroxy-
bridged complex (R,R/S,S)-[(NNOtBu)In(Cl)(μ-OH)]2.17,19a
The meso complex can only be formed if the (R,R/R,R)- and
(S,S/S,S)-5 dissociate during the reaction. Also, when 5 is
dissolved in neat methanol or isopropanol at room temper-
ature, the NMR spectra of the resulting products show
resonances corresponding to the quantitative formation of
new metal methoxide and isopropoxide complexes (Figure
1
S46). Integration of the H NMR spectra of these new species
clearly shows that the complexes maintain a monoalkoxy-
bridged dinuclear structure analogous to complex 5.
◆
■
( ) observed PLA Mn ( ) as functions of
added 1 for polymerization of LA with catalysts 5 ([5] = 0.0024 M,
CD2Cl2, room temperature; Mn = number averaged molecular weight).
Figure 9. Plots of kobs
The reactivity with alcohols and water shows that dinuclear
complexes such as 5 are undergoing some dissociation in the
presence of added species. Indeed, cross over reactions between
( )-[(NNOtBu)InCl]2(μ-Cl)(μ-OEt) (5) and (NNOMe)InCl2
(3), as well as [(NNOMe)InI]2(μ-I)(μ-OEt) (7) and the
(NNOtBu)InI2 (2), are observed in 5 min (Figures S47, S48). A
similar crossover reaction was observed between meso-
[(NNOMe)In(I)(μ-OEt)]2 (meso-8) and ( )-(NNOtBu)InI2
(2) (Figure S49).
The potential lability of the dinuclear catalysts is not a factor
in lactide polymerization. If the dinuclear complex 5 is dormant
and dissociation to an active mononuclear species is required
for polymerization (Scheme 2a), addition of [NNOtBu]InCl2
(1) should shift the equilibrium toward the unreactive species
and affect polymerization rates and/or polymer molecular
weights. In a series of experiments, different amounts of 1 were
added to a solution of 5 (CD2Cl2, 25 °C) prior to the addition
of monomer to the catalyst mixture, and the polymerization
was monitored by 1H NMR spectroscopy. In an identical set of
reactions, the polymer was isolated and analyzed. The resulting
values of kobs and Mn remain constant with up to 5 additional
equiv of 1 (Figure 9). At higher concentrations of 1, the
solution becomes saturated. These experiments indicate that,
although complex 5 can dissociate in the presence of donors,
this dissociation does not play a role in the polymerization of
lactide.
DISCUSSION AND CONCLUSIONS
■
We have synthesized a family of dinuclear ethoxy-bridged
indium complexes [(NNOR)InX]2(μ-OEt)(μ-Y) (R = t-Bu,
Me; X = Cl, I; Y = Cl, I, OH, OEt) and their enantiopure
analogues, and compared the reactivity of mono- (Y = Cl, I)
and bis-alkoxy-bridged (Y = OEt) complexes for the living ring-
opening polymerization (ROP) of lactide (LA). In particular,
the chloro-ethoxy-bridged derivative [(NNOtBu)InCl]2(μ-
OEt)(μ-Cl) (5) is one of the most successful catalysts for
controlled LA ROP and generates PLA samples of greater than
350 kDa with predictable molecular weights and low molecular
weight distributions. The living nature of the propagation was
confirmed by in situ monitoring of reactions as well as by
analysis of bulk polymer samples. Kinetics studies show that
after an induction period, the rate of lactide polymerization is
first order in the concentration of lactide and also first order in
the concentration of catalyst. Importantly, the second-order
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Scheme 6. Dissociation of Bulkier Dinuclear Catalysts with Added Lactide19b
Scheme 7. Competing Coordination and Ring-Opening in the Reactivity of (R,R/R,R)-5 with rac-LA
rate constants are the same regardless of whether one or two
bridging ethoxy groups are present.
enantiopure analogues of the bis-ethoxy-bridged complex. The
solid-state structure of [(NNOR)In(I)(OEt)]2 derived from
( )-H(NNOR) (Figure 1) is in the centrosymmetric meso
form, while the enantiopure (S,S/S,S)-8 has lost the center of
symmetry (Figure 4). These differences are reflected in the
solution structures of the compounds: (R,R/R,R)- and (S,S/
Complex 5 is a unique asymmetrically bridged dinuclear
catalyst with excellent potential as a commercial catalyst for the
ring-opening polymerization (ROP) of lactide (LA).38 The
dinuclear nature of the catalyst raises an important mechanistic
question: Is the propagating species derived from the
dissociation of the dimer in the presence of a large
concentration of lactide, or does the dinuclear complex itself
act as the propagating species? The data presented above
support a dinuclear propagating species.
The Ethoxy-Bridged Indium Complexes Are Dinuclear
in Solution. Indium alkoxide complexes in this family are
invariably dinuclear in the solid state. A variety of techniques
(VT NMR spectroscopy, 2D NOESY spectroscopy, PGSE
experiments) confirm that the complexes are also dinuclear in
solution and that the solution structures correlate closely to the
solid state structures. This is most striking when comparing the
1
S,S)-8 have a H NMR signature different from that of meso-8
(Figure 3).
There is ample evidence that the dinuclear complexes
dissociate in solution and can react with added donors under
forcing conditions; however, the dinuclear complexes are the
thermodynamic sinks in these systems. All irreversible reactions
with added donors/complexes (Scheme 5) as well as
conversion of enantiopure to meso complexes (Figure S21)
result in the formation of more stable dinuclear complexes. The
most telling experiment is the low reactivity of complex 5 with
neat pyridine at 100 °C. Thus, addition of a large concentration
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of a donor such as lactide does not necessarily lead to
dissociation of the dimer.
however, the polymer obtained in the polymerization or rac-LA
with this catalyst is atactic.
An alternate mechanism that better explains this phenom-
enon involves two competing rates: the rate of coordination of
L- and D-LA to the catalyst (kL and kD) and the rates of
propagation of these monomers (k2L and k2D) (Scheme 7). We
know that k2L/k2D is 14 for (R,R/R,R)-5. However, these values
were determined using enantiopure catalyst and enantiopure
monomer. When racemic lactide is added, there will be a
competition between coordination of D- or L-LA to (R,R/R,R)-
5. We propose that kD > kL and that the equilibrium favors the
formation of the adduct (R,R/R,R)-5·D-LA, which goes on to
ring open D-LA. If the rates kD and k2L are on the same order,
we would expect an equal incorporation of L- and D-LA into the
polymer to form atactic PLA. This mechanism is compatible
with the nonlinear decrease in the polymerization rate for rac-
LA with increasing enantiopurity of catalyst (Figure 8a). We are
assuming that for ROP of rac-LA with (R,R/R,R)-5, chain end
control is surpassed by the high selectivity of the catalyst. With
( )-5 and with all isomers of 8, chain end control dominates to
yield similar Pm values (∼0.6).
In conclusion, we studied the polymerization behavior and
selectivity of chiral alkoxy-bridged dinuclear indium complexes
for the ring-opening polymerization of lactide. We were able to
show that the complexes remain dinuclear during lactide
polymerization, with a stable dinuclear polymeryl-bridged
steady state that resists chain termination and leads to a highly
controlled system. The dinuclear nature of the chiral catalyst
has a significant effect on the stereoselectivity of the catalysts
and will impact the design of future indium-based catalysts.
Polymerization Rate and Polymer Molecular Weight
Are Not Affected by Addition of (NNOtBu)InCl2. Although
an equilibrium between 5, 1, and a mononuclear ethoxy
complex (NNOtBu)In(OEt)(Cl) is possible, it does not affect
the rate of polymerization nor the molecular weights of the
resulting polymers (Figure 9). If complex 5 was a dormant
species requiring dissociation to complex 1 and an active
(NNOtBu)In(OEt)(Cl), then addition of 1 would be expected
to shift the equilibrium toward complex 5 and, in turn, lower
rates of polymerization and lead to higher observed molecular
weights. The lack of influence of added 1 on the reaction rates
and polymer properties confirms that an equilibrium between
the dinuclear complex 5 and the monometallic compounds 1
and (NNOtBu)In(OEt)(Cl), if it is indeed present, is not
important to propagation, and thus complex 5 is not a dormant
species, but rather a dinuclear active catalyst as shown in
Scheme 2B.
There Is No Evidence for Dissociation of 5 during
Polymerization. The mechanism in Scheme 2A assumes that
the induction period is caused by the dissociation of
[(NNOtBu)InCl]2(μ-Cl)(μ-OEt) (5) to give lactide adducts of
(NNOtBu)In(OEt)(Cl), the proposed active catalyst, and
(NNOtBu)InCl2 (1) in the presence of lactide. We have never
observed complex 1 in solution during polymerization (Figure
S50); however, we have observed such dissociation in bulkier
systems. In a related work with bulky N-alkylated ligands, the
dinuclear catalyst [(NnPrNO)InCl]2(μ-Cl)(μ-OEt) dissociates
in the presence of added lactide to form [(NnPrNOtBu)In(Cl)-
(O-polymer) and (NnPrNOtBu)InCl2 (Scheme 6).19b Interest-
ingly, in the bulkier systems that dissociate, all stereoselectivity
for polymerization of rac-LA is lost, suggesting that the
selectivity observed for complex 5 is a result of its dinuclear
nature.
The Mono- and Bis-Alkoxy-Bridged Complexes Show
Different Selectivities for the ROP of Lactide. One of the
most striking pieces of evidence for the dinuclear nature of the
propagating species is the difference of selectivities observed for
the mono- and bis-ethoxy bridged complexes 5 and 8. If the
propagating species is a mononuclear alkoxide, then complexes
5 and 8 should have identical selectivities. A comparison of
polymerization rates with (R,R/R,R)-5 (Table 3, entry 5) and
(R,R/R,R)-8 (Table 4, entry 5) shows Pm values of 0.48 and
0.65, respectively. Indeed, the different krel values for 5 and 8
(14 vs 2), and the general independence of selectivity on
catalyst chirality for complex 8, indicate that the two catalysts
cannot have identical propagating species. The different
solution structures of the dinuclear complexes, matched by
the solid-state structures, are a strong justification for their
different selectivities. The nonlinear nature of the dependence
of the observed rate constant on enantiopurity of 5 (Figure 7a)
also supports a dinuclear propagating species.
These observations lead us to propose an alternate
mechanism for the ring-opening polymerization of lactide by
our dinuclear catalysts. It is clear that ethoxy-bridged indium
complexes of the type [(NNOR)InX]2(μ-OEt)(μ-Y) (X = Cl, I;
Y = Cl, I, OH, OEt) remain dinuclear during the ROP of LA.
However, our studies show that the mechanism depicted in
Scheme 2B is too simplistic to explain the selectivities observed
for this system. In particular, there is a high krel value for
polymerization of L-LA as compared to D-LA with (R,R/R,R)-5;
EXPERIMENTAL SECTION
■
General Considerations. Unless otherwise indicated, all air- and/
or water-sensitive reactions were carried out under dry nitrogen using
either an MBraun glovebox or standard Schlenk line techniques. NMR
spectra were recorded on a Bruker Avance 400 and 600 MHz
1
spectrometer. H NMR chemical shifts are reported in ppm versus
residual protons in deuterated solvents as follows: δ 7.27 CDCl3, δ
5.32 CD2Cl2. 13C{1H} NMR chemical shifts are reported in ppm
versus residual 13C in the solvent: δ 77.2 CDCl3, δ 54.0 CD2Cl2.
Diffraction measurements for X-ray crystallography were made on a
Bruker X8 APEX II diffraction with graphite monochromated Mo Kα
radiation. The structures (Table S3) were solved by direct methods
and refined by full-matrix least-squares using the SHELXTL
crystallographic software of Bruker-AXS. Unless specified, all non-
hydrogen were refined with anisotropic displacement parameters, and
all hydrogen atoms were constrained to geometrically calculated
positions but were not refined. EA CHN analysis was performed using
a Carlo Erba EA1108 elemental analyzer. The elemental composition
of unknown samples was determined by using a calibration factor. The
calibration factor was determined by analyzing a suitable certified
organic standard (OAS) of a known elemental composition. Molecular
weights were determined by triple detection gel permeation
chromatography (GPC-LLS) using a Waters liquid chromatograph
equipped with a Water 515 HPLC pump, Waters 717 plus
autosampler, Waters Styragel columns (4.6 × 300 mm) HR5E, HR4
and HR2, Water 2410 differential refractometer, Wyatt tristar
miniDAWN (laser light scattering detector), and a Wyatt ViscoStar
viscometer. A flow rate of 0.5 mL min−1 was used, and samples were
dissolved in tetrahydrofuran (THF) (2 mg mL−1). Narrow molecular
weight polystyrene standards were used for calibration purposes.
Materials. Solvents (THF, toluene, hexane, and diethyl ether) were
collected from an MBraun Solvent Purification System whose columns
are packed with activated alumina. CH2Cl2 and CHCl3 were dried over
CaH2 and degassed through a series of freeze−pump−thaw cycles.
CD2Cl2, CDCl3, methanol, ethanol, isopropanol, ethyl acetate,
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pyridine, and acetonitrile (CH3CN) were dried over CaH2, collected
by vacuum distillation, and degassed through a series of freeze−
pump−thaw cycles. rac-LA ([α]D = −0.1°, toluene, 25 °C), D-LA
([α]D = +287 to +300°, toluene, 25 °C), and L-LA ([α]D = −288.1°,
toluene, 25 °C) were gifts from PURAC America Inc. and were
recrystallized twice from hot dried toluene prior to use. (1R,2R)- or
(1S,2S)-1,2-diaminocyclohexane was resolved from ( )-trans-1,2-
diaminocyclohexane followed by the literature procedures.39 KOEt
was generated by reacting KOtBu with dried ethanol. The solvent was
removed under high vacuum, and addition of hexane to the residual
precipitates a white solid. The white solid, KOEt, was isolated by
vacuum filtration and dried in vacuo for 4 h. 1,3,5-Trimethoxybenzene
and tetrakis(trimethylsilyl)silane (TMSS) were purchased from
Aldrich and Alfa Aesar, respectively, and used as received. para-
Methyl salicaldimine (see the Supporting Information), proligand
H(NNOtBu), and complexes 1, 2, and 5 were synthesized according to
previously reported procedures.17,31
characterization. A suspension of InCl3 (81.6 mg, 0.37 mmol) in THF
(3 mL) was added dropwise to a slurry of K(NNOMe) (147 mg, 0.37
mmol) in THF (10 mL). The mixture was stirred for 16 h at room
temperature resulting in a white solid (KCl) and yellow solution. The
white solid was filtered through Celite, and the pale yellow filtrate was
concentrated under vacuum. The residue was taken up in 3 mL of
Et2O, from which an off-white solid precipitated. The solid was
isolated by vacuum filtration and dried in vacuo for a few hours. (S,S)-
(NNOtBu)InCl2, yield (153 mg, 76%). 1H NMR (600 MHz, CD2Cl2):
δ 7.28 (1H, br s, ArH), 6.89 (1H, br s, ArH), 4.14 (2H, br s, NH−
CH2−Ar), 2.73 (3H, s, N−(CH3)2), 2.54−2.69 (3H, m, −NH− and
−CH− of DACH), 2.44 (3H, br s, −N−(CH3)2), 2.01−2.13 (2H, m,
−CH2− of DACH), 1.82−1.98 (2H, m, −CH2− of DACH), 1.42 (9H,
br s, Ar−(CH3)3), 1.16−1.36 (13H, m, −CH2− of DACH and Ar−
(CH3)3). 13C{1H} NMR (151 MHz, CD2Cl2): δ 164.1 (Ar C), 140.2
(Ar C), 130.4 (Ar C−H), 125.3 (Ar C−H), 125.3 (Ar C), 121.9 (Ar
C), 66.7 (N−CH−CH2), 56.0 (N−CH−CH2), 52.4 (N−CH2−Ar),
44.6 (N(CH3)2), 38.1 (N(CH3)2), 35.6 (Ar−C(CH3)3), 34.5 (Ar−
C(CH3)3), (32.0 (Ar−C(CH3)3), 31.9 (−CH2− of DACH), 30.2 (Ar−
C(CH3)3), 25.0 (2C, −CH2− of DACH), 22.5 (−CH2− of DACH).
(S,S)-(NNOtBu)InCl2, Anal. Calcd for C23H39Cl2InN2O: C, 50.66; H,
7.21; N, 5.14. Found: C, 50.57; H, 7.06; N, 5.14. (R,R)-(NNOtBu)-
InCl2, yield (231 mg, 80%) based on 211 mg of (R,R)-K(NNOtBu).
Anal. Calcd for C23H39Cl2InN2O: C, 50.66; H, 7.21; N, 5.14. Found:
C, 50.39; H, 7.20; N, 5.39.
Synthesis of 6-tert-Butyl-2-{N-[2-(N,N-dimethyl)-
aminocyclohexyl]salicaldimino}-4-methylphenol ( )-H-
(NNOMe), (R,R)-, and (S,S)-H(NNOMe). A 500 mL round-bottom
flask was charged with para-methyl salicaldimine (2.87 g, 9.08 mmol)
(see the Supporting Information) in 150 mL of acetonitrile. NaBH4
(2.51 g, 66.3 mmol) was added to the stirring mixture. The reaction
mixture was stirred for 30 min, and a 1.5 mL solution of glacial acetic
acid was added dropwise to the stirring mixture. The reaction mixture
was stirred for 16 h. After the basic aqueous workup with 1 M NaOH
and 5% MeOH/CH2Cl2, the organic layer was collected, and the off-
white solid was obtained by removal of the solvent under vacuum. The
solid was recystallized from acetronitrile (2.17 g, 78%). 1H NMR (600
MHz, CDCl3): δ 7.01 (1H, br s, ArH), 6.74 (1H, br s, ArH), 4.01 (d,
Synthesis of (NNOMe)InCl2 (3). A 100 mL round-bottom flask was
charged with H(NNOMe) (309 mg, 0.97 mmol) in toluene (30 mL) at
room temperature. Benzyl potassium (126 mg, 0.97 mmol) in toluene
(30 mL) was added dropwise to the stirring solution at room
temperature. The reaction mixture was stirred for 16 h. An off-white
solid was isolated by removal of the solvent under high vacuum. The
product, K(NNOMe), was used further in the reaction without any
other purification and characterization. A suspension of InCl3 (239 mg,
1.08 mmol) in THF (3 mL) was added dropwise to a slurry of
K(NNOMe) in THF (10 mL). The mixture was stirred for 16 h at
room temperature, resulting in a white solid (KCl) and yellow
solution. The white solid was filtered through Celite, and the pale
yellow filtrate was concentrated under vacuum. The residue was taken
up in 5 mL of Et2O, from which an off-white solid precipitated. The
solid was isolated by vacuum filtration and dried in vacuo for a few
hours. Recrystallization with a mixture solution of THF and ether at
4
4
1H, JH−H = 13.4 Hz, NH−CH2−Ar), 3.81 (1H, d, JH−H = 13.4 Hz,
NH−CH2−Ar), 3.38 (1H, br s, −NH−), 2.36−2.43 (1H, m, −CH− of
DACH), 2.25−2.33 (4H, m, Ar−CH3; −CH− of DACH), 2.23 (6H, s,
−N(CH3)2), 2.14−2.20 (1H, m, −CH2− of DACH), 1.80−1.89 (2H,
m, −CH2− of DACH), 1.68−1.75 (1H, m, −CH2− of DACH), 1.45
(9H, br s, Ar−(CH3)3), 1.11−1.29 (4H, m, −CH2− of DACH).
13C{1H} NMR (151 MHz, CDCl3): δ 154.8 (Ar C), 136.4 (Ar C),
126.6 (Ar C−H), 126.5 (Ar C−H), 126.1 (Ar C), 124.3 (Ar C), 66.6
(CH−N(CH3)2), 58.9 (CH−NH−CH2), 51.1 (N−CH−CH2), 40.0
(N(CH3)2), 34.5 (N(CH3)2), 34.5 (Ar−C(CH3)3), 31.7 (Ar−CH3),
29.6 (Ar−C(CH3)3), 25.3 (−CH2− of DACH), 20.9 (−CH2− of
DACH), 20.8 (−CH2− of DACH). ( )-H(NNOMe), Anal. Calcd for
C20H34N2O: C, 75.42; H, 10.76; N, 8.80. Found: C, 75.36; H, 10.72;
N, 8.87. (R,R)-H(NNOMe), yield (0.75 g, 52%) based on 1.44 g of
(R,R)-para-tert-butyl salicaldimine. Anal. Calcd for C20H34N2O: C,
75.42; H, 10.76; N, 8.80. Found: C, 75.25; H, 10.76; N, 8.69. (S,S)-
H(NNOMe), yield (0.42 g, 50%) based on 0.83 g of (S,S)-para-methyl
salicaldimine. Anal. Calcd for C20H34N2O: C, 75.42; H, 10.76; N, 8.80.
Found: C, 75.07; H, 10.62; N, 8.45.
Synthesis of 4,6-Di-tert-butyl-2-{N-[2-(N,N-dimethyl)-
aminocyclohexyl]salicaldimino}phenol (R,R)- and (S,S)-H-
(NNOtBu). The syntheses were carried out in a manner analogous to
that of the racemic compound above and have identical NMR
signatures.17 (R,R)-H(NNOtBu), yield (1.88 g, 59%) based on 3.14 g of
(R,R)-para-tert-butyl salicaldimine. Anal. Calcd for C23H40N2O: C,
76.61; H, 11.18; N, 7.77. Found: C, 76.44; H, 11.29; N, 7.65. (S,S)-
H(NNOtBu), yield (0.35 g, 50%) based on 0.70 g of (S,S)-para-tert-
butyl salicaldimine. Anal. Calcd for C23H40N2O: C, 76.61; H, 11.18; N,
7.77. Found: C, 75.10; H, 11.23; N, 7.84.
1
room temperature afforded yellow crystals of 3 (380 mg, 76%). H
NMR (400 MHz, CD2Cl2): δ 7.04 (1H, d, 4JH−H = 2.0 Hz, ArH), 6.68
4
2
(1H, d, JH−H =1.7 Hz, ArH), 4.46 (1H, d, JH−H = 12.6 Hz, NH−
CH2−Ar), 3.97 (1H, dd, 2JH−H = 12.5 Hz, 3JH−H = 6.7 Hz, NH−CH2−
Ar), 2.73−2.82 (1H, m, −CH− of DACH), 2.71 (3H, s, −N−
(CH3)2), 2.63−2.61 (1H, m, −CH− of DACH), 2.54 (1H, br s,
−NH− of DACH), 2.38−2.48 (1H, m, −CH2− of DACH), 2.27 (3H,
s, −N−(CH3)2), 2.21 (3H, s, Ar−CH3), 1.94−2.04 (m, 1H, −CH2− of
DACH), 1.78−1.94 (2H, m, −CH2− of DACH), 1.40 (9H, Ar−
(CH3)3), 1.18−1.29 (4H, m, −CH2− of DACH). 13C{1H} NMR (151
MHz, CD2Cl2): δ 161.9 (Ar C), 140.2 (Ar C), 129.7 (Ar C-H), 125.0
(Ar C−H), 128.9 (Ar C), 121.4 (Ar C), 66.2 (N−CH2−Ar), 54.8 (N−
CH−CH2), 51.0 (N−CH−CH2), 44.7 (N(CH3)2), 38.4 (N(CH3)2),
35.3 (Ar−C(CH3)3), 31.5 (Ar−CH3), 30.3 (Ar−C(CH3)3), 25.0
(−CH2− of DACH), 22.4 (−CH2− of DACH), 20.9 (−CH2− of
DACH). Anal. Calcd for C20H33Cl2InN2O: C, 47.74; H, 6.61; N, 5.57.
Found: C, 47.48; H, 6.60; N, 5.51.
Synthesis of ( )-, (R,R)-, and (S,S)-(NNOMe)InI2 (4). Complex 4
was synthesized in a manner similar to that of 3 by adding a
suspension of InI3 (973 mg, 1.96 mmol) in THF (3 mL) to a slurry of
K(NNOMe) (700 mg, 1.96 mmol) in THF (20 mL). Complex 4 was
obtained on a glass frit and dried in vacuo for a few hours (965 mg,
Synthesis of (R,R)- and (S,S)-(NNOtBu)InCl2 (1). The syntheses of
( )- and (R,R)-NNOtBu)InCl2 were published previously in the
literature.17 (S,S)-(NNOtBu)InCl2 was carried out in a manner
analogous to that of ( )- and (R,R)-(1), and they have identical
1
4
NMR signatures. A 20 mL scintillation was charged with H(NNOMe
)
72%). H NMR (600 MHz, CD2Cl2): δ 7.04 (1H, d, JH−H = 1.8 Hz,
4
(198 mg, 0.62 mmol) in toluene (5 mL) at room temperature. Benzyl
potassium (76.8 mg, 0.59 mmol) in toluene (5 mL) as a slurry was
added dropwise to the stirring solution at room temperature. The
reaction mixture was stirred for 16 h. An off-white solid was isolated by
removal of the solvent under high vacuum. The product, K(NNOtBu),
was used for further reaction without any other purification and
ArH), 6.70 (1H, d, JH−H = 1.5 Hz, ArH), 4.05−4.11 (1H, m, NH−
CH2−Ar), 3.94 (1H, d, JH−H = 11.1 Hz, NH−CH2−Ar), 2.72−2.78
2
(1H, m, −CH− of DACH), 2.63−2.69 (1H, m, −CH− of DACH),
2.61 (3H, s, −N−(CH3)2), 2.54−2.58 (1H, m, −CH2− of DACH),
2.45 (3H, s, −N−(CH3)2), 2.21 (3H, s, Ar−CH3), 2.06−2.11 (1H, m,
−CH2− of DACH), 1.81−1.96 (2H, m, −NH−; −CH2− of DACH),
12768
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1.76 (1H, m, −CH2− of DACH), 1.42 (9H, Ar−(CH3)3), 1.17−1.40
(4H, m, −CH2− of DACH). 13C{1H} NMR (151 MHz, CD2Cl2): δ
161.3 (Ar C), 140.9 (Ar C), 129.0 (Ar C−H), 128.6 (Ar C−H), 125.6
(Ar C), 122.7 (Ar C), 65.5 (N−CH2−Ar), 56.7 (N−CH−CH2), 52.4
(N−CH−CH2), 43.9 (N(CH3)2), 37.7 (N(CH3)2), 35.1 (Ar−
C(CH3)3), 32.4 (Ar−CH3), 30.6 (Ar−C(CH3)3), 25.1 (−CH2− of
DACH), 25.0 (−CH2− of DACH), 23.1 (−CH2− of DACH), 21.0
(−CH2− of DACH). ( )-(NNOMe)InI2, Anal. Calcd for
C20H33I2InN2O: C, 35.01; H, 4.85; N, 4.08. Found: C, 35.11; H,
4.79; N, 4.08. (R,R)-(NNOMe)InI2, The syntheses were carried out in
a manner analogous to that of the racemic compound above and have
identical NMR signatures. Yield (286 mg, 85%) based on 173 mg of
(R,R)-K(NNOMe). Anal. Calcd for C20H33I2InN2O: C, 35.01; H, 4.85;
N, 4.08. Found: C, 34.90; H, 4.85; N, 4.03. (S,S)-(NNOMe)InI2, The
syntheses were carried out in a manner analogous to that of the
racemic compound above and have identical NMR signatures. Yield
(162 mg, 80%) based on 105 mg of (S,S)-K(NNOMe). Anal. Calcd for
C20H33I2InN2O·CH3CN: C, 36.34; H, 4.99; N, 5.78. Found: C, 36.32;
H, 4.97; N, 5.23.
Synthesis of (R,R/R,R)- and (S,S/S,S)-[(NNOtBu)InCl]2(μ-Cl)(μ-
OEt) (5). The syntheses were carried out in a manner analogous to
that of the racemic compound and have identical NMR signatures.17
(R,R/R,R)-5, yield (28 mg, 87%) based on 32 mg of (R,R)-
(NNOtBu)InCl2. Anal. Calcd for C48H84Cl3In2N4O3: C, 52.40; H,
7.60; N, 5.09. Found: C, 51.97; H, 7.54; N, 4.95. (S,S/S,S)-5, yield (53
mg, 85%) based on 61 mg of (S,S)-(NNOtBu)InCl2. Anal. Calcd for
C48H84Cl3In2N4O3: C, 52.40; H, 7.60; N, 5.09. Found: C, 52.16; H,
7.51; N, 5.34.
4.41 (1 H, m, O−CH2−CH3), 3.65−3.77 (1H, m, NH−CH2−Ar),
3.41 (1H, d, 3JH−H = 10.8 Hz, −NH−), 2.60−2.72 (1H, m, −CH− of
DACH), 2.57 (3H, s, −N(CH3)2), 2.51−2.55 (1H, m, −CH2− of
3
4
DACH), 2.46 (1H, td, JH−H = 11.4 Hz, JH−H = 3.2 Hz, −CH− of
DACH), 2.20 (3H, s, −Ar−CH3), 1.96 (3H, s, −N(CH3)2), 1.84 (2H,
3
t, JH−H = 12.1 Hz, −CH2− of DACH), 1.43 (9H, Ar−(CH3)3), 1.37
3
(2H, t, JH−H = 12.1 Hz, O−CH2−CH3), 1.05−1.33 (5H, m, −CH2−
of DACH). 13C{1H} NMR (101 MHz, CD2Cl2): δ 163.4 (Ar C),
139.7 (Ar C), 130.5 (Ar C−H), 128.4 (Ar C−H), 122.9 (Ar C), 120.3
(Ar C), 67.4 (N−CH2−Ar), 61.9 (O−CH2−CH3), 53.2 (N−CH−
CH2), 50.0 (N−CH−CH2), 46.0 (N(CH3)2), 38.1 (N(CH3)2), 35.3
(Ar−C(CH3)3), 31.2 (Ar−CH3), 30.4 (Ar−C(CH3)3), 25.4 (−CH2−
of DACH), 25.2 (−CH2− of DACH), 22.6 (−CH2− of DACH), 20.9
(−CH2− of DACH), 19.5 (O−CH2−CH3). Anal. Calcd for
C42H71I3In2N4O3: C, 39.09; H, 5.55; N, 4.34. Found: C, 42.69; H,
6.22; N, 5.48.
Synthesis of (meso)-, (R,R/R,R)-, and (S,S/S,S)-[(NNOMe)In(I)(μ-
OEt)]2 (8). A suspension of KOEt (24.5 mg, 0.29 mmol) in toluene (4
mL) was added dropwise to a stirring suspension of 4 (125.4 mg, 0.14
mmol) in toluene (6 mL) at room temperature (both of the solutions
were stirred for 5 min separately prior to addition). The pale yellow
color of the reaction mixture changed to white in 5 min after the
addition of KOEt. The white solid was filtered through a glass filter
paper to collect the colorless filtrate complex 8, which was dried in
vacuo to yield an off white residue. THF (1 mL) was added to the
white residue, forming a suspension. Subsequently, acetonitrile (2 mL)
was added to this stirring suspension to solubilize any remaining
impurities. The suspension was filtered through a glass frit, and the
solid was washed with acetonitrile (2 × 1 mL) and dried under
vacuum to obtain the desired complex 8 as a white solid (81.2 mg,
Synthesis of [(NNOMe)InCl]2(μ-Cl)(μ-OEt) (6). A solution of
NaOEt (20 mg, 0.30 mmol) in toluene (1.5 mL) was added dropwise
to a stirring suspension of complex 3 (150 mg, 0.30 mmol) in toluene
(3 mL) at room temperature. The reaction mixture was stirred for 12
h. The resulting white precipitate was filtered through Celite to yield a
pale yellow filtrate. All volatiles were removed in vacuo, and ether (5
mL) was added to the residue to precipitate an off-white solid. The
product was collected on a glass frit by vacuum filtration, washed with
ether at least twice, and dried in vacuo for a few hours (140.8 mg,
1
74% yield). H NMR (400 MHz, CD2Cl2): δ 6.98 (1H, br s, ArH),
2
6.59 (1H, br s, ArH), 5.08 (1H, d, JH−H = 13.3 Hz, NH−CH2−Ar),
4.30−4.42 (1H, m, O−CH2−CH3), 3.65−3.80 (2H, m, O−CH2−
CH3, NH−CH2−Ar), 2.60−2.75 (5H, br s, −CH− of DACH; −CH−
of DACH; −N(CH3)2), 2.49 (1H, m, −NH− of DACH), 2.18 (3H, s,
Ar−CH3), 2.06 (3H, s, −N(CH3)2), 1.97 (1H, br m, −CH2− of
DACH), 1.74−1.87 (2H, m, −CH2− of DACH), 1.39 (9H, Ar−
(CH3)3), 1.05−1.23 (8H, m, −CH2− of DACH and O−CH2−CH3).
13C{1H} NMR (151 MHz, CD2Cl2): δ 163.5 (Ar C), 139.7 (Ar C),
130.4 (Ar C−H), 128.4 (Ar C−H), 122.4 (Ar C), 120.0 (Ar C), 68.3
(N−CH−CH2), 60.8 (O−CH2−CH3), 52.6 (N−CH2−Ar), 51.4 (N−
CH−CH2), 49.9 (N(CH3)2), 40.0 (N(CH3)2), 35.3 (Ar−C(CH3)3),
31.1 (Ar−CH3), 30.4 (Ar−C(CH3)3), 25.4 (−CH2− of DACH), 25.1
(−CH2− of DACH), 23.3 (−CH2− of DACH), 20.9 (−CH2− of
DACH), 19.7 (O−CH2−CH3). (meso)-8, Anal. Calcd for
C44H76I2In2N4O4: C, 43.73; H, 6.34; N, 4.64. Found: C, 44.09; H,
6.36; N, 4.84.
1
93%). H NMR (400 MHz, CD2Cl2): δ 6.99 (1H, br s, ArH), 6.60
(1H, br s, ArH), 4.91 (1H, d, 2JH−H = 13.5 Hz, NH−CH2−Ar), 4.25−
4.45 (1 H, m, O−CH2−CH3), 3.72 (1H, dd, 2JH−H = 13.6 Hz, 3JH−H
=
3
4
1.7 Hz, NH−CH2−Ar), 2.86 (1H, td, JH−H = 11.3, JH−H = 3.1 Hz,
−CH− of DACH), 2.73−2.74 (1H, br m, −NH−), 2.66 (3H, s,
−N(CH3)2), 2.52−2.63 (1H, m, −CH− of DACH), 2.48−2.50 (1H,
m, −CH2− of DACH), 2.18 (3H, s, Ar−CH3), 2.03 (3H, s,
−N(CH3)2), 1.86−1.99 (1H, m, −CH2− of DACH), 1.82 (2H, br
m, −CH2− of DACH), 1.39 (9H, Ar−(CH3)3), 1.01−1.31 (6H, m,
−CH2− of DACH; O−CH2−CH3). 13C{1H} NMR (101 MHz,
CD2Cl2): δ 163.2 (Ar C), 139.9 (Ar C), 130.6 (Ar C−H), 128.6 (Ar
C−H), 123.3 (Ar C), 120.0 (Ar C), 65.3 (N−CH2−Ar), 63.0 (O−
CH2−CH3), 53.2 (N−CH−CH2), 50.8 (N−CH−CH2), 44.6 (N-
(CH3)2), 38.5 (N(CH3)2), 35.5 (Ar−C(CH3)3), 31.5 (Ar−CH3), 30.2
(Ar−C(CH3)3), 25.4 (−CH2− of DACH), 25.2 (−CH2− of DACH),
22.4 (−CH2− of DACH), 20.9 (−CH2− of DACH), 19.8 (O−CH2−
CH3). Anal. Calcd for C42H71Cl3In2N4O3: C, 49.65; H, 7.04; N, 5.51.
Found: C, 48.91; H, 6.89; N, 5.29.
(R,R/R,R)- and (S,S/S,S)-8. The syntheses were carried out in a
manner analogous to that of the racemic compound above. (R,R/R,R)-
8, yield (48 mg, 60%) based on 90 mg of (R,R)-(NNOMe)InI2. Anal.
Calcd for C44H76I2In2N4O4: C, 43.73; H, 6.34; N, 4.64. Found: C,
44.11; H, 6.31; N, 4.65. (S,S/S,S)-8, yield (44 mg, 68%) based on 73
mg of (S,S)-(NNOMe)InI2. Anal. Calcd for C44H76I2In2N4O4: C, 43.73;
H, 6.34; N, 4.64. Found: C, 43.96; H, 6.34; N, 4.67. (R,R)- and (S,S)-8
1
have identical NMR spectra. H NMR (600 MHz, CDCl3): δ 7.02
(2H, m, ArH), 6.65−6.70 (1H, m ArH), 6.53−6.61 (1H, m, ArH),
Synthesis of [(NNOMe)InI]2(μ-I)(μ-OEt) (7). NaOEt (61.3 mg,
0.90 mmol) suspended in toluene (6 mL) was added dropwise to a
stirring suspension of complex 4 (309.4 mg, 0.45 mmol) in toluene (8
mL) (both of the suspensions were stirred for 5 min separately). The
reaction mixture was stirred for 16 h. The resulting white precipitate
was filtered through glass filter paper to collect the pale yellow filtrate.
All volatiles were removed from the filtrate in vacuo, and the residue
was completely dissolved in THF (2 mL). Acetonitrile (5 mL) was
added to this solution after which complex 8 was isolated as a white
solid via filtration. The solvent was removed from the filtrate to yield
complex 7 as an off-white solid. Both complexes were washed with
acetonitrile (2 × 1 mL) and dried in vacuo for several hours (complex
2
5.19 (1H, d, JH−H = 13.6 Hz, NH−CH2−Ar), 4.63−4.72 (1H, m,
NH−CH2−Ar), 4.33−4.49 (2H, m, O−CH2−CH3), 3.82−3.96 (2H,
m, O−CH2−CH3), 3.70−3.82 (2H, m, NH−CH2−Ar), 2.95−3.09
(1H, m, −CH− of DACH), 2.73−2.80 (1H, m, −CH− of DACH),
2.60−2.73 (m, 4H, −NH− of DACH and −N(CH3)2), 2.52 (1H, d,
3JH−H = 10.9 Hz, −NH− of DACH), 2.44 (3H, s, −N(CH3)2), 2.34
3
(3H, s, −N(CH3)2), 2.27 (1H, td, JH−H = 3.8, 11.7 Hz, −NH− of
DACH), 2.19−2.25 (6H, m, Ar−CH3), 2.10−2.19 (2H, m −CH2− of
DACH), 2.09 (3H, s, −N(CH3)2), 1.98 (1H, m, −CH2− of DACH),
1.78−1.91 (4H, m, −CH2− of DACH), 1.42 (19H, m, −CH2− of
3
DACH, Ar−C(CH3)3), 1.30 (3H, t, JH−H = 6.7 Hz, O−CH2−CH3),
1
3
7, 100.5 mg, 35% yield; complex 8, 39.5 mg, 14% yield). H NMR
1.14−1.28 (6H, m, −CH2− of DACH), 1.11 (3H, t, JH−H = 6.6 Hz,
(400 MHz, CD2Cl2): δ 7.00 (1H, d, 4JH−H = = 1.9 Hz, ArH), 6.63 (1H,
O−CH2−CH3), 1.07 (1H, m, −CH2− of DACH), 0.93−1.00 (1H, m,
4
d, JH−H = 1.9 Hz, ArH), 4.79−4.86 (1H, m, NH−CH2−Ar), 4.15−
−CH2− of DACH). 13C{1H} NMR (151 MHz, CD2Cl2): δ 164.0 (Ar
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C), 163.0 (Ar C), 139.4 (Ar C), 138.7 (Ar C), 130.0 (Ar C−H), 129.6
(Ar C−H), 128.0 (Ar C−H), 127.8 (Ar C−H), 122.1 (Ar C), 121.9
(Ar C), 121.2 (Ar C), 119.4 (Ar C), 67.8 (N−CH−CH2), 64.6 (N−
CH−CH2), 60.9 (O−CH2−CH3), 60.5 (O−CH2−CH3), 56.2 (N−
CH−CH2), 52.1 (N−CH−CH2), 51.2 (N−CH2−Ar), 47.4 (N−CH2−
Ar), 46.6 (−N(CH3)2), 45.3 (−N(CH3)2), 39.7 (−N(CH3)2), 38.5
(−N(CH3)2), 35.0 (Ar−C(CH3)3), 34.9 (−CH2− of DACH), 30.7
(Ar−C(CH3)3), 30.4(Ar−C(CH3)3), 30.1 (Ar−C(CH3)3), 28.8
(−CH2− of DACH), 25.1 (−CH2− of DACH), 25.1 (−CH2− of
DACH), 24.7 (−CH2− of DACH), 24.6 (−CH2− of DACH), 23.9
(−CH2− of DACH), 22.7 (−CH2− of DACH), 20.8 (Ar−CH3), 20.7
(Ar−CH3), 20.1 (O−CH2−CH3), 19.5 (O−CH2−CH3).
the solution. The reaction was stirred for 1 h, and after that the
mixture was evaporated to dryness in vacuo. The residue was washed
with diethyl ether and dried for 2 h in vacuo, to yield complex 11 as a
white powder. Suitable crystals for X-ray diffraction were grown by
slow diffusion on diethyl ether in a CH2Cl2 solution of the complex
(204.1 mg, 85% yield). 1H NMR (600 MHz, CD2Cl2): δ 7.20 (1H, d,
4
4JH−H = 3 Hz, ArH), 6.78 (1H, d, JH−H = 3 Hz, ArH), 4.81 (1H, d,
2JH−H = 13.2 Hz, NH−CH2−Ar), 4.14−4.44 (1H, m, O−CH2−CH3),
2
3
3.73 (1H, d, JH−H = 13.3 Hz, NH−CH2−Ar), 3.42 (1H, d, JH−H
=
10.8 Hz, −NH−), 2.56−2.65 (1H, m, −CH− of DACH), 2.54 (3H, s,
−N(CH3)2), 2.50 (1H, m, −CH2− of DACH), 2.39−2.47 (1H, m,
−CH− of DACH), 1.91 (3H, s, −N(CH3)2), 1.82 (2H, m, −CH2− of
DACH), 1.36−1.47 (12H, m, Ar−(CH3)3; O−CH2−CH3), 1.20−1.32
(11H, m, Ar−(CH3)3; −CH2− of DACH), 1.02−1.18 (3H, m,
−CH2− of DACH). 13C{1H} NMR (151 MHz, CD2Cl2): δ 163.1 (Ar
C), 138.8 (Ar C), 136.6 (Ar C−H), 126.8 (Ar C−H), 124.5 (Ar C),
119.8 (Ar C), 67.2 (N−CH2−Ar), 62.0 (O−CH2−CH3), 53.2 (N−
CH−CH2), 50.2 (N−CH−CH2), 46.0 (N(CH3)2), 38.1 (N(CH3)2),
35.6 (Ar−C(CH3)3), 34.3 (Ar−C(CH3)3), 32.1 (Ar−C(CH3)3), 31.1
(Ar−C(CH3)3), 30.4 (−CH2− of DACH), 25.4 (−CH2− of DACH),
25.2 (−CH2− of DACH), 22.7 (−CH2− of DACH), 19.6 (O−CH2−
CH3). Anal. Calcd for C48H84I3In2N4O4: C, 45.46; H, 6.64, N, 4.43.
Found: C, 45.13; H, 6.64; N, 4.40.
Synthesis of [(NNOtBu)In(I)(μ-OEt)]2 (9). A 25 mL round-bottom
flask was charged with a suspension of NaOEt (56 mg, 0.84 mmol) in
5 mL of THF. A solution of 2 (300 mg, 0.42 mmol) dissolved in 10
mL of THF was added dropwise to this mixture. After the reaction
mixture was stirred for 2 h at room temperature, NaI formation was
observed. The salt was removed by filtration through glass filter paper,
and the remaining yellow solution was evaporated to dryness. The
residue was washed with hexane and dried for 2 h in vacuo to yield
1
complex 9 as a white powder (208 mg, 76% yield). H NMR (600
MHz, CD2Cl2): δ 7.20 (1H, br s, ArH), 6.76 (1H, br s, ArH), 5.10
2
(1H, d, JH−H = 13.4 Hz, NH−CH2−Ar), 4.28−4.40 (1H, m, O−
CH2−CH3), 3.69−3.82 (2H, m, O−CH2−CH3, NH−CH2−Ar),
2.67−2.71 (5H, m, −CH− of DACH; −CH− of DACH; −N(CH3)2),
2.48−2.50 (1H, m, −NH−), 2.18 (3H, s, Ar−CH3), 2.04 (3H, s,
−N(CH3)2), 1.96 (1H, br m, −CH2− of DACH), 1.76−1.90 (2H, m,
−CH2− of DACH), 1.40 (9H, Ar−(CH3)3), 1.26 (9H, m, Ar−
(CH3)3), 1.13−1.23 (5H, m, −CH2− of DACH; O−CH2−CH3),
1.02−1.13 (3H, −CH2− of DACH). 13C{1H} NMR (151 MHz,
CD2Cl2): δ 162.2 (Ar C), 137.7 (Ar C), 135.0 (Ar C−H), 125.8 (Ar
C−H), 123.3 (Ar C), 118.5 (Ar C), 67.1 (N−CH2−Ar), 59.8 (O−
CH2−CH3), 51.6 (N−CH−CH2), 50.7 (N−CH−CH2), 44.7 (N-
(CH3)2), 39.0 (N(CH3)2), 34.6 (Ar−C(CH3)3), 33.2 (Ar−C(CH3)3),
31.1 (Ar−C(CH3)3), 30.0 (Ar−C(CH3)3), 29.5 (−CH2− of DACH),
24.6 (−CH2− of DACH), 24.2 (−CH2− of DACH), 22.3 (−CH2− of
DACH), 18.9 (O−CH2−CH3). Anal. Calcd for C50H86I2In2N4O4: C,
46.44; H, 6.65; N, 4.33. Found: C, 46.41; H, 6.60; N, 4.34.
Representative NMR Scale Polymerization with 5, 6, 7, 8,
and 10. A Teflon-sealed NMR tube was charged with a 0.25 mL
solution of a catalyst stock solution (0.25 mL, 5, 6, 7, 10, 0.0091 M,
0.0023 mmol; 8, 0.00228 M, 0.00057 mmol) in CDCl3 and made up
to 0.5 mL with a 0.25 mL solution of CDCl3, and the solution was
mixed and frozen in a glovebox using a liquid N2 cold wall. A stock
solution of rac-lactide (0.91 M, 0.46 mmol for 5, 6, 7, 10; 0.228 M,
0.114 mmol for 8) and an internal standard 1,3,5-trimethoxybenzene
(5 mg, 0.03 mmol for 5, 6, 7, 10; 1.2 mg, 0.0075 mmol for 8) in 0.5
mL of CDCl3 were added to the frozen complex solution and frozen
again, forming a bilayer. The NMR tube was sealed and quickly
evacuated by vacuum to remove N2 gas from the NMR tube. Two
solutions were thawed and quickly mixed before the NMR tube was
loaded into the NMR spectrometer (400 MHz Avance Bruker
spectrometer). The polymerization was monitored to 90% conversion.
Representative Large-Scale Polymerization with Complex 5.
A 20 mL scintillation vial was charged with a solution of complex 5
(1.0 mg, 0.00091 mmol) in 2 mL of CH2Cl2. A solution of rac-lactide
(131 mg, 0.91 mmol) in 2 mL of CH2Cl2 was added dropwise to the
vial. The resulting mixture was stirred at room temperature for 16 h.
The resulting clear solution was concentrated to dryness. A sample of
the residue was dissolved in CDCl3 to be analyzed by 1H NMR
spectroscopy to determine conversion. The remaining polymeric
material was dissolved in a minimum amount of CH2Cl2 (1 mL) and
added to cold wet methanol (0 °C, 7 mL). The polymer precipitated
from solution and was isolated by centrifugation. The supernatant was
decanted, and the polymer was dried under high vacuum for 2 h prior
to analysis.
Synthesis of [(NNOMe)InI]2(μ-OH)(μ-OEt) (10). Deoxygenated
H2O (0.6 μL, 0.033 mmol) was added to a stirring suspension of
complex 8 (50 mg, 0.041 mmol) in THF (3 mL) at room temperature.
The reaction mixture was stirred for 16 h. The solvent was removed in
vacuo to obtain a white solid, which was dried under vacuum to yield
complex 10 as a white solid. To purify the compound, this solid was
redissolved in THF (2 mL), and a 3 mL solution of acetonitrile was
added to the solution to precipitate the unreacted starting complex.
This suspension was filtered through a frit, and complex 8 was
collected as a solid and reused for other reactions. The filtrate was
isolated, and the solvent was removed to yield complex 10 as a while
solid (19.5 mg, 50% yield). 1H NMR (600 MHz, CD2Cl2): δ 6.97 (1H,
d, 4JH−H = 1.9 Hz, ArH), 6.61 (1H, d, 4JH−H = 1.7 Hz, ArH), 4.77−4.82
(1H, m, NH−CH2−Ar), 4.13−4.39 (1H, m, O−CH2−CH3), 3.69
1
2
3
Procedure for in Situ Crossover between 3 and 5. H NMR
(1H, dd, JH−H = 13.6 Hz, JH−H = 2.2 Hz, NH−CH2−Ar), 3.39 (1H,
d, J = 10.9 Hz, −NH−), 2.61−2.66 (1H, m, −CH− of DACH), 2.55
(3H, s, −N(CH3)2), 2.47−2.53 (1H, m, −CH2− of DACH), 2.43 (1H,
spectroscopy (400 MHz NMR spectrometer, CD2Cl2 at room
temperature) was used to monitor the crossover of complexes 3 and
5. In a glovebox, a solution of complex 3 (0.5 mL, 0.0045 M) was
loaded to a Teflon-sealed NMR tube and frozen in a liquid N2 cold
well (−90 °C). A solution of complex 5 (0.5 mL, 0.0046 M) was
added to the frozen solution of complex 3 and frozen again, forming a
bilayer. Two solutions were thawed and quickly mixed before the
NMR tube was loaded into the NMR spectrometer.
Procedure for in Situ Crossover between (R,R/R,R)- and (S,S/
S,S)-8. 1H NMR spectroscopy (400 MHz NMR spectrometer, CDCl3
at room temperature) was used to monitor the crossover of (R,R/
R,R)- and (S,S/S,S)-8. In a glovebox, a solution of (R,R/R,R)-8 (0.5
mL, 0.62 mM) was loaded into a Teflon-sealed NMR tube and frozen
in a liquid N2 cold well (−90 °C). A solution of (S,S/S,S)-8 (0.5 mL,
0.62 mM) was added to the frozen solution of (R,R/R,R)-8 and frozen
again, forming a bilayer. Two solutions were thawed and quickly mixed
before the NMR tube was loaded into the NMR spectrometer.
3
4
td, JH−H = 11.4 Hz, JH−H = 3.3 Hz, −CH− of DACH), 2.18 (3H, s,
3
Ar−CH3), 1.94 (3H, s, −N(CH3)2), 1.82 (2H, t, JH−H = 15.9 Hz,
3
−CH2− of DACH), 1.41 (9H, Ar−(CH3)3), 1.34 (2H, t, JH−H = 7.0
Hz, O−CH2−CH3), 1.01−1.33 (5H, m, −CH2− of DACH). 13C{1H}
NMR (101 MHz, CD2Cl2): δ 163.3 (Ar C), 139.7 (Ar C), 130.5 (Ar
C−H), 128.4 (Ar C−H), 122.9 (Ar C), 120.3 (Ar C), 67.3 (N−CH2−
Ar), 61.9 (O−CH2−CH3), 53.2 (N−CH−CH2), 49.9 (N−CH−CH2),
46.0 (N(CH3)2), 38.1 (N(CH3)2), 35.3 (Ar−C(CH3)3), 31.2 (Ar−
CH3), 30.3 (Ar−C(CH3)3), 25.4 (−CH2− of DACH), 25.1 (−CH2−
of DACH), 22.6 (−CH2− of DACH), 20.9 (−CH2− of DACH), 19.5
(O−CH2−CH3). Anal. Calcd for C42H71I3In2N4O3: C, 42.73; H, 6.15;
N, 4.75. Found: C, 43.26; H, 6.20; N, 5.40.
Synthesis of [(NNOtBu)InI]2(μ-OH)(μ-OEt) (11). A 25 mL round-
bottom flask was charged with a solution of 5 (250 mg, 0.19 mmol) in
10 mL of CH2Cl2, and then water (3.5 μL, 0.19 mmol) was added to
12770
dx.doi.org/10.1021/ja3048046 | J. Am. Chem. Soc. 2012, 134, 12758−12773

Journal of the American Chemical Society
Article
Procedure for in Situ Reactivity of ( )-5 with 2 equiv of
ASSOCIATED CONTENT
* Supporting Information
Full solid-state and solution characterization of complexes as
well as kinetics and stereoselectivity studies of polymerization
(Figures S1−S50). This material is available free of charge via
the Internet at http://pubs.acs.org.
■
1
Pyridine, Ethyl Acetate, Water, and Ethanol. H NMR spectros-
S
copy (400 MHz NMR spectrometer, CDCl3 at room temperature)
was used to monitor the reactivity of ( )-5 with pyridine, ethyl
acetate, water, and ethanol. In a glovebox, a solution of complex 5
(0.25 mL, 0.0023 M) was loaded into a Teflon-sealed NMR tube and
made up to 0.5 mL with a 0.25 mL solution of CDCl3. The solution
was mixed and frozen in the glovebox using a liquid N2 cold wall (−90
°C). A solution of pyridine (0.5 mL, 0.0046 M) was added to the
frozen solution of ( )-5 and frozen again, forming a bilayer. The
solutions were thawed and quickly mixed before the NMR tube was
loaded into the NMR spectrometer.
AUTHOR INFORMATION
Corresponding Author
mehr@chem.ubc.ca
■
Notes
Procedure for in Situ Reactivity of ( )-5 with 10 equiv of
1
The authors declare no competing financial interest.
Pyridine. H NMR spectroscopy ((400 MHz NMR spectrometer),
CD2Cl2 at variable temperatures (300−180 K)) was calibrated by 4%
methanol in methanol-d4 prior to each sample measurement. In a
glovebox, a solution of complex 5 (0.5 mL, 0.0023 M) was loaded into
a Teflon-sealed NMR tube and made up to 0.5 mL with a 0.25 mL
solution of CD2Cl2, and a solution of pyridine (0.5 mL, 0.023 M) was
added to the solution of ( )-5. The solutions were mixed at room
temperature, and the NMR tube was loaded into the NMR
spectrometer.
ACKNOWLEDGMENTS
■
We thank UBC, NSERC, CFI, and BCKDF for funding, C. C.
Yan, T. Janes, K. Rebullar, and S. Bishop for the synthesis of
starting materials, and Dr. M. Ezhova for her technical
assistance with the NMR spectroscopy. I.Y. acknowledges
Brian Patrick for valuable discussions on solving some
structures.
Procedure for Reactivity of ( )-5 with Neat Methanol,
Isopropanol, and Pyridine. A 20 mL scintillation vial was charged
with ( )-5 (5.0 mg, 0.0045 mmol), and approximately 5 mL of alcohol
was added to the vial. The mixture was stirred for 16 h at room
temperature. The solvent was removed under vacuum, and the
resulting white solid was washed with hexane and further dried in
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Representative Sample Preparation with ( )-5 for PGSE
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