exploiting non-covalent interactions for room temperature ......complexes and thus have been applied...
TRANSCRIPT
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Exploiting Non-Covalent Interactions for Room
Temperature Heteroselective rac-Lactide
Polymerization Using Aluminium Catalysts.
S. Gesslbauer,a R. Savela,b Y. Chen,a A. J. P. White,a C. Romaina*
a Department of Chemistry, Molecular Sciences Research Hub (MSRH), Imperial College
London, W12 0BZ, London, UK.
b Laboratory of Organic Chemistry, Åbo Akademi University, FI-20500 Åbo, Finland.
ABSTRACT Whereas harnessing non-covalent interactions (NCIs) have largely been applied to
late-transition metal complexes and to the corresponding catalytic reactions, there are very few
examples showing the importance of NCIs in early-transition metal and main group metal
catalysis. Here, we report on the effects of hydrogen bond donors in the catalytic pocket to explain
the high activity and stereoselectivity of a series of aluminium catam complexes in rac-lactide
ring-opening polymerisation (ROP). Four original aluminium catam catalysts have been
synthetized and fully characterized. Structure-activity relationships and isotope effect show the
importance of the NH moieties of the ligand in rac-lactide ROP. Computational studies highlight
beneficial hydrogen bonds between the ligand and the monomer. Overall, structural
characterization of the catalysts, mechanistic, kinetic and computational studies support the
benefits of non-covalent interactions in the catalytic pocket.
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TOC graphic
KEYWORDS Ring-Opening Polymerisation, rac-Lactide, Aluminium Catalysts, Non-Covalent
Interactions, Hydrogen bond.
Non-Covalent Interactions (NCIs) encompass various types of interactions including ion pair
interactions, hydrogen bonding, dipolar interactions, π−π interactions, hydrophobic interactions,
and Van der Waals interactions.1 They are found to be of importance in biology, chemistry, and
material science among others. Related to chemistry and catalysis, NCIs are ubiquitous in
organocatalysis and the so-called hydrogen bond catalysis.2, 3 There has been a growing interest in
harnessing NCIs in metal catalysis to increase catalyst activity and selectivity. As highlighted in
recent reviews, different approaches have been reported exploiting ligand-ligand interactions,
ligand-substrate interactions and more sophisticated scenarios involving multiple interactions with
a third species.1, 3-5 However, most of these strategies have been applied to late-transition metal
complexes and thus have been applied to organic reactions catalysed by such metals (i.e.
hydrogenation, hydroformylation, allylation reactions to name a few) as well as in polymerisation
catalysis. For example, in olefin polymerisation, non-covalent attractive interactions have been
proposed to explain the livingness of some post-metallocene catalysts due to C-H⸱⸱⸱F-C
interactions between the “fluorinated” ligand and the growing polymer chain.6, 7 Interestingly,
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there are very few examples highlighting the importance of NCIs in early transition metal and
main group metal catalysis. For example, Peters and co-workers reported cooperative Lewis
Acid/Ion Pair catalysis. Thus, a series of Al complexes bearing a salen-type ligand with tethered
ammonium salts were found to outperform the corresponding “untethered” catalysts in the
asymmetric synthesis of β-lactones and the carbocyanation of aldehydes.8, 9
With this in mind, we decided to focus on new main group metal complexes bearing ligand(s)
capable of forming NCIs of interest in polymerisation catalysis. The “catechol-amine” ligand
scaffold (referred to as “catam”) is a good candidate as it offers two rigid o-aminophenolate
moieties for coordination to high oxidation state and oxophilic metals as well as two NH moieties
near the metal centre as potential hydrogen bond donors (Figure 1).10, 11 Whereas salen-, salan-
and salalen-type ligands have been thoroughly studied in lactide ring-opening polymerisation
(ROP), less investigations have been carried out on the catam analogues where the nitrogen atoms
are directly connected to the aryl moieties.12, 13 To the best of our knowledge, only titanium and
zirconium complexes bearing a catam-type ligand [i.e. a phenylenediamine bis(phenolate)] have
been investigated in lactide ROP.12 We recently reported the first series of aluminium catam
complexes which was found able to catalyse rac-lactide ROP at room temperature;13 a rather rare
feature for aluminium-based catalysts.14-17 Here, we report the benefit of hydrogen bond donors in
the catalytic pocket to explain the high activity and stereoselectivity of a new family of aluminium
catam complexes in rac-lactide ROP. Structural characterization of the catalysts, mechanistic,
kinetic (including isotope effect) and computational studies highlight the benefit of such non-
covalent interactions.
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Figure 1: Representative structures of catam-type ligand scaffold and corresponding Al
complexes.
Complex synthesis and characterization.
Figure 2: synthesis of complex 1-4.
The tethered o-aminophenol H2HL was prepared according to standard literature procedure using
3,5-di-tert-butyl catechol and 2,2-dimethyl-1,3-propanediamine in acetonitrile.18 Subsequently,
H2HL reacts with one equivalent of AlEt3 in THF to cleanly afford the corresponding aluminium
ethyl complex HLAl(Et) 1 in good yield (56 %, Figure 2). The 1H NMR spectrum (C6D6, 298 K)
shows a C2-symmetric structure in solution with, among others, a characteristic shielded triplet
and quartet peaks for the Al ethyl chain (δ1H = 1.19 ppm and δ1H = -0.05 ppm) along with signals
at 2.98 ppm attributed to the NH groups (Figure S6). The molecular structure of 1 has been
confirmed by X-Ray diffraction of a single crystal obtained by diffusion of pentane into a
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concentrated THF solution. As illustrated in Figure 3, the pentacoordinated aluminium atom
exhibits an almost perfect square pyramidal geometry (τ5 = 0.03)19 with a planar coordination of
the tetradendate ligand and the ethyl chain on the apical position. The 6-membered ring formed by
the (N’N’Al) chelate adopts a chair conformation with both NH bonds in axial position pointing
out in the same direction. This offers two orientationally-defined H-bond donors spaced by 2.79(1)
Å as observed in well-known squaramide-type organocatalysts.20 A similar ligand conformation
was observed in a Pd(II) complex reported by Wieghardt and co-workers.18 Two molecules of THF
were found forming a hydrogen bond with the NH groups of the ligands [H7⋅⋅⋅O40 = 2.231(4) Å
and H11⋅⋅⋅O50 = 2.181(6) Å] unambiguously confirming the ability of the ligand to act as a H-
bond donor.
Figure 3: The crystal structure of 1 (ellipsoid plot 50% probability, H omitted except on the NH
moieties) showing the N–H···O hydrogen bonds to the included tetrahydrofuran solvent
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molecules. The hydrogen bonding geometries [N···O and H···O (Å), and N–H···O (°)] are
3.110(2), 2.231(4) and 165.6(13) for the N7·· ·O40 contact, and 3.061(2), 2.181(4) and 165.4(12)
for the N11···O50 contact. Distance H7··· H11 is 2.79(1).
1 was found to react with 1 equivalent of iso-propanol (iPA) in THF at room temperature to
afford the corresponding Al isopropoxide derivative HLAl(OiPr) 2. 1H NMR spectrum at 298K
shows a set of broad signals attributed to a main compound featuring a C2-symmetric structure in
solution. The DOSY NMR spectrum in d8-THF (solvent used for room temperature
polymerisation) exhibits a monomeric species (Figure S15) in accordance with the proposed
structure (Figure 2). Similarly, DOSY NMR analysis carried out in C6D6 in the presence of 10
equivalent of iPA (conditions for “immortal” polymerisations) shows a mononuclear complex with
potential coordination of iPA (Figure S18). However, in the absence of coordinative molecules
(i.e. THF, iPA), the DOSY NMR spectrum in C6D6 suggests the existence of both mononuclear
and dinuclear species in equilibrium (Figure S17).
In order to assess the importance of the NH moiety, a N-methylated ligand was synthesised with
the aim to increase the steric bulk around the metal centre and to potentially improve the
stereocontrol during the polymerisation. Following an adapted procedure from literature (using
nBuLi and MeI), a methylated version H2MeL of the pro-ligand H2HL was obtained and
subsequently reacted with AlEt3 in THF overnight to afford the corresponding methylated complex
MeLAl(Et) 3 (Figure 2). The 1H NMR spectrum of 3 shows a C2-symmetric structure in solution
with, amongst others, one singlet δ1H = 2.58 ppm (C6D6, 24 °C) for the two N-methyl groups
(Figure S8). Unambiguously, the molecular structure of 3 has been determined by X-Ray
diffraction of a single crystal (Figure 4) obtained from a cold THF/pentane mixture (-40 °C).
Contrary to 1, the molecular structure of 3 exhibits a pentacoordinated aluminium atom adopting
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a distorted trigonal bipyramidal geometry (τ5 = 0.63)19 with the two phenolate moieties trans to
each other [O-Al-O = 169.2(11) °] and with both Al–O vectors approximately orthogonal to the
N2Al chelate plane. This results in longer Al-O bonds and shorter Al-N bonds in complex 3 [Al1-
O1 = 1.859(3) Å, Al1-O17 =1.854(3) Å, Al1-N7 = 2.034(3) Å and Al1-N11 = 2.054(3) Å] than in
complex 1 [Al1-N7 = 2.1057(14) Å, Al1-N11 = 2.1142(14) Å, Al1-O1 = 1.8175(12) Å, Al1-
O17=1.8176(13) Å]. The 6-membered ring formed by the (N’N’Al) chelate adopts a distorted
twisted boat conformation with both methyl groups in equatorial position.
Figure 4: The crystal structure of 3 (ellipsoid plot 50% probability, H omitted) showing a
pentacoordinated aluminium atom adopting a distorted trigonal bipyramidal geometry (τ5 = 0.63).
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rac-lactide polymerisation. Complex 2 (either directly or generated in-situ from the addition of
iPA to 1) was found to be active for rac-lactide ROP at room temperature in THF (2/rac-LA =
1/100, 90 min., 91% conv.) to afford well-defined heterotactic PLA (Pr ∼ 0.9). The polymerisation
is well-controlled (Table 1), i.e.: i) linear increase of molar masses with monomer conversion
(Figure S21), ii) low dispersity (Ð) and iii) pseudo first order in monomer with kHobs = (4.75 ±
0.29) x 10-4 s-1 (Figure S20). Analysis of the polymers by MALDI-ToF mass spectrometry shows
the presence of an isopropoxide end-group, in line with a polymerisation occurring via a well-
known coordination-insertion mechanism (Figure S30).
Table 1: rac-lactide polymerisation using 1-4.
Entry Cat.
Cat./ iPA/ LA
( eq.)
Solvent T
(°C)
Time
(min)
Conv.a
(%)
Mn(SEC)(Ð)b
(kg/mol) Prc
Mn(calc.)d
(kg/mol)
1 1 1/1/100 THF 25 90 92.5 10.8 (1.3) 0.90 13.3
2e 1 1/1/100 THF 25 15 + 120
85.3 7.3 (1.2) 0.89 12.3
3 2 1/0/100 THF 25 90 91.4 9.5 (1.3) 0.91 13.2
4 3 1/1/100 THF 25 (50)
180 (240)
0
(0)
-
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-
-
-
-
5 4 1/0/100 THF 25 90 83.9 16.5 (1.3) 0.91 11.8
6 Hsalan-Alf 1/1/100 Toluene 90 960 46.1 5.7 (1.3) 0.54 6.6
7 Salen-Alg,21 1/0/100 Toluene 70 300 94 21.2 (1.1)i 0.08 -
8 2 1/9/1000 Toluene 90 30 90.4 11.5 (1.1) 0.61 13.0
9 2 1//4/500 THF 50 60 55.8 7.0 (1.2) 0.85 8.0
10 2 1/0/250 Bulkh 130 3.5 40.8 4.3 (1.1) 0.61 5.9
11 Salen-Al22 1/0/300 Bulk 130 30 25 14.3 (1.1)i 0.09 -
Reaction conditions: [LA]0 = 1 mol.L-1; a) Determined by 1H NMR by relative integration of signals at 5.06 ppm (monomer) and 5.20 ppm (polymer); b) Determined by SEC calibrated with
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polystyrene standards in THF and corrected by a factor of 0.58;23 c) Probability of racemic linkages determined by 1H NMR spectroscopy; d) Calculated using the conversion; e) 1 was generated in-situ by stirring AlEt3 and H2HL1 in THF for 15 minutes prior to the addition of LA and iPA; f) salan derivative of 1, see ESI; g) salen derivative of 1 with BnO instead of OiPr,24 h) in molten monomer, i) Determined by SEC calibrated with polystyrene standards in CHCl3, value not corrected.22
Interestingly, examples of Al complexes leading to highly heterotactic PLA (Pr > 0.80) are
scarce and formation of isotactic PLA usually prevails.25-32 Gibson and co-workers reported PLA
with Pr up to 0.98 using an aluminium salan-type catalyst.33 More recently, Jones and Kol
separately reported a series of aluminium pyrolidine Schiff base catalysts affording highly
heterotactic PLA with Pr = 0.87 and Pr = 0.98, respectively.34, 35 The observed heterotacticity is
likely due to a chain-end control (i.e. the last inserted monomer in the polymer chain drives the
insertion of the next one) with the presence of NCIs in the catalytic pocket which reinforces the
chiral environment. In our previous work, we observed that the catam aluminium complexes
bearing a somewhat more rigid ligand (ethyl backbone) led to slightly isotactic PLAs.13 This
change in selectivity can be attributed to the different ligand flexibility which can favor a different
mechanism (e.g. site-control). Further systematic modifications of the ligand backbone will be
explored to rationalize the influence of the ligand and improve catalyst design. The activity at room
temperature (< 30 °C) is particularly notable as aluminium complexes usually require elevated
temperature (> 70 °C) to be significantly active. In addition to our previous aluminium catam
complex series, only two other types of aluminium-based catalytic systems with significant activity
at room temperature were previously reported, i.e.: i) an heterobimetallic aluminium-lithium
complex featuring an anionic aluminium supported by a NON-type diamido ether tridentate ligand,
and ii) in-situ generated anionic aluminium complexes bearing salen- or porphyrinato-type ligands
in the presence of epoxide (CHO, PO) and ammonium halide salt.14-17 However, 2 is the first
example of a well-defined discrete monometallic aluminium catalyst exhibiting both significant
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heteroselectivity and activity at room temperature (< 30 °C) for rac-lactide. In comparison, the
analogous aluminium salen and Hsalan complexes featuring the same propyl backbone displayed
lower activities at higher temperatures (>70 °C) than catalyst 1 and 2 at room temperature (Table
1, entry 6-7 and Figure S10).21, 22, 24 These results highlight key features of the catam ligand
scaffold, i.e.: i) the rigid o-aminophenolate moieties forming a 5-membered (O’N’Al) chelate
which has previously been found to be of importance in ε-CL and lactide ROP;13, 36 ii) the NH
group directly connected to the aryl moiety which can act as hydrogen-bond donor due to more
polarized N-H bonds than in the corresponding Hsalan ligand.
Exploring the potential of these new aluminium catalysts, 2 was found to be active at low loading
(as low as 0.1 mol. %) and in the presence of alcohol acting as chain-transfer agent (conditions
close to “immortal” conditions) while maintaining its high stereoselectivity at higher temperature
(50 °C in THF, Pr = 0.85) leading to a very active system able to polymerise ∼ 250 eq. of rac-LA
in 1h (TOF = 250 h-1, Table 1, entry 9). 2 also shows high activity in toluene at 90 °C (TOF = 1800
h-1) and in molten monomer at 130 °C (TOF = 1700 h-1) with well-controlled molar masses and
low dispersities (Table 1, Entry 8 and 10 respectively). However, the polymers obtained under
these conditions were atactic due to the high temperature which reduces monomer selectivity. The
catalytic system can also be generated in-situ by initially reacting the pro-ligand H2HL and AlEt3
in THF for 15 minutes before addition to a rac-LA/iPA mixture in THF (Table 1). Heterotactic
polymers were obtained without significant loss of activity and stereoselectivity compared to the
isolated catalyst 2 (Table 1, entry 2 and 3).
The pro-ligand H2HL has also been tested in rac-lactide polymerization in the presence of
sparteine and isopropanol as per standard organocatalyzed-reaction conditions (Table S1).37 The
resulting catalytic system was able to slowly polymerize rac-LA at room temperature (5 mol. %
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of H2-HL, 27% rac-LA conv., 24h, r.t.) to afford atactic PLA. In the absence of either sparteine or
isopropanol, the catalytic system was found inactive. These results highlight the ability of the
ligand scaffold to form hydrogen-bonds to promote lactide ROP. In similar conditions, the
H2Hsalan-based catalytic system was found to be inactive (Table S1). This supports the importance
of the NH group directly connected to the aryl moieties in the catam ligand scaffold. Changing
solvent from dichloromethane to tetrahydrofuran shows a decrease in activity in accordance with
competitive hydrogen bonding with the substrates.
Surprisingly, complex 3 was inactive for rac-lactide ROP as per conditions previously
investigated for complex 1 and 2. No activity was observed, neither at room temperature nor at 50
°C in THF in the presence of 1 equivalent of iPA and 100 eq. of rac-lactide (Table 1, entry 4). This
confirms the importance of the NH moieties in complexes 1 and 2, either by enabling the complex
to adopt a suitable geometry for polymerisation and/or by forming favourable non-covalent
interactions (NCI), such as hydrogen bonds observed in the molecular structure of complex 1
(Figure 3). In the same vein, Merkhodavandi and co-workers reported indium complexes where
substitution of a secondary amine by a tertiary amine in the ligand scaffold led to a decrease of the
catalyst activity by two orders of magnitude for lactide ROP.38 Jones and co-workers observed
different “wrappings” of salan ligands around an Al centre due to a weak interaction between a
NH moiety of the ligand and an isopropoxide oxygen atom.29
Thus, to further highlight the importance of the NH moieties of the ligand, deuterated derivatives
of H2HL and complex HLAl(OiPr) 2 were synthesised, i.e. D2DL and DLAl(OiPr) 4 (see details in
ESI). 4 was found to be an active catalyst for rac-LA ROP at room temperature (kDobs = 2.52 x 10-
4 s-1) as per conditions used for 2. As previously observed with 2, the polymerization is well-
controlled and leads to heterotactic PLA (Table 1, entry 5). Kinetic studies show that the catalyst
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2 is almost twice as fast as the deuterated catalyst 4 (i.e. kH / kD .= 4.75x10-4 / 2.52x10-4 ~ 1.9,
Table 1 entry 3 and 5) confirming the importance of the NH moieties of the ligand in the catalyst
activity (Figure 5). These results suggest a secondary kinetic isotope effect (KIE) with a remote
effect rather than breaking of a NH/D bond. The fairly high value of 1.9 (for a secondary KIE
only) is likely due to equilibrium or binding isotope effects (EIE/BIE) in agreement with binding
of the monomer with the NH moieties in the catalytic pocket.39
0 2000 4000 6000
0
1
2
3
ln(L
A0/L
At)
Time (sec)
catalyst 2
catalyst 4
Figure 5: Plot showing the isotope effect observed between 2 and 4 for rac-lactide ROP.
Computational studies. In order to get a better understanding of the mechanism, DFT
calculations were carried out using ωB97xD/6-31G(d,p) which includes a second-generation
dispersion correction and solvation model (see computational details in supporting information).40
For computational simplicity, the reaction between an aluminium methoxide complex I(c) whose
structure has been deduced from the molecular structure of 1 (ethyl group replaced by a methoxide
group) and one or two molecules of lactide has been studied for the initiation and propagation
step, respectively. Different approaches and coordination of the L-lactide molecule onto the
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catalyst as well as molecules of THF and alcohol have been considered and are summarized in the
supporting information (Figures S32-S34). Only the most favorable pathway will be discussed. In
line with the experimental results showing a well-controlled ROP, a standard coordination-
insertion mechanism was envisaged and divided in two processes, i.e. initiation (first monomer
insertion) and propagation (second monomer insertion).15, 26, 29, 41-45
Initiation mechanism and non-covalent interactions (NCI). During the initiation step, it was
found that the L-lactide can displace coordinated molecules of THF (∆∆G = -1.5 kcal/mol, Figure
S40-41)46 and docks on the top of the catalyst due to favourable NCIs with the ligand and the metal
centre, including a hydrogen bond between one oxygen atom of the lactide carbonyl and one NH
bond of the ligand as highlighted in the NCI surfaces in Figure 6 (bright blue dot).47 This suitably
orientates the monomer and possibly contributes to its activation by decreasing the electron density
on the carbon atom of the carbonyl in a similar manner as H-bonding activation by ROP
organocatalysts (e.g. urea-based catalytic systems).48-51 These steric and electronic factors favor
the subsequent nucleophilic attack by the Al-OMe bond onto the lactide carbonyl via a transition
state III(t)-TS with ∆G298 = 6.9 kcal/mol on the PES (Figure 7). Similarly, intermediate V(t) shows
a hydrogen bond between one oxygen atom of the hemiacetal and one NH bond sticking out of the
catalytic pocket. This suitably orientates the hemiacetal for the subsequent ring-opening via the
second transition state VI(c)-TS with ∆G298 = 9.2 kcal/mol. Overall, the initiation step features a
low energy barrier of 14.4 kcal/mol and shows the existence of hydrogen bonds between the
“substrate” (reacting monomer) and the NH moieties of the ligand. The calculated KIE values
(~1.1) are lower than the experimental value (~1.9) but in accordance with a normal isotope effect
as experimentally observed (Figure S46-S48). Such a difference can be due to BIE/EIE.39
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Figure 6: Intermediate II(c) showing docking of the L-lactide on the top of the initiator (left) and
NCI surface of II(c) showing a hydrogen bond between an O atom of L-lactide and one NH bond
of the ligand (right).
Framework Distortion Energy (FDE). As recently studied by Tolman, Cramer and co-workers,
energetically low cost ligand distortion has been found to be a key feature in rationalizing and
predicting catalyst activity for cyclic ester ROP.43, 52-55 This can be accessed by calculating the
Framework Distortion Energy (FDE) which estimates the energy penalty incurred when distorting
the ligand geometry of the “catalyst” to the geometry adopted in the rate-determining or turnover-
limiting transition state (TOL TS). Thus, considering I(c) as the catalyst and VI(t)-TS as the TOL
TS, we found a low FDE of 5.8 kcal/mol56 which features among the lowest FDE reported for
similar tetradentate Al complexes investigated for cyclic ester ROP. This is in line with the low
energy barriers calculated and the high activity observed at room temperature. It should be
mentioned that in both transition states III(t)-TS and VI(t)-TS, the 6-membered (N’N’Al) chelate
adopts a twisted conformation which was found to be slightly more favorable than the chair
conformation adopted in III(c)-TS and VI(c)-TS (∆∆G ~ 3 kcal/mol and 6 kcal/mol, respectively).
Interestingly, VI(c)-TS shows a significantly higher FDE than VI(t)-TS (8.0 kcal/mol and 4.5
Hydrogen bond
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kcal/mol for VI(c)-TS and VI(t)-TS, respectively) suggesting that the twisted conformation
adopted by the ligand in the TS is more favorable than the chair conformation.
Topographic Steric Map (TSM). Among the various molecular descriptors used to depict
catalytic reactions, Cavallo and co-workers introduced topographic steric maps to characterize the
shape of a catalytic pocket.57 Based on the buried volume in a considered sphere centered on an
active site (here, the metal center), these maps give an estimation of the accessible molecular
surface along with a shape of the catalytic pocket and the interaction surface between the catalyst
and the substrate. This has previously been successfully used to rationalize various catalytic
reactions, including Al-catalyzed cyclic ester ROP. Thus, the steric maps for I(c) and II(C) show
a relatively flat space with the two NH slightly sticking out from the surface and suitably orientated
to form hydrogen bonds (Figure 8). This could explain the favorable “docking” of the L-lactide
on the top of the catalyst and be at the origin of the binding isotope effect.39 Similarly, the steric
map of VI(c)-TS shows that most of the free space (up to 80% of the free volume) is located in
the “South-East quadrant” where the reaction happens and one of the NH is directly pointing
toward this free space (Figure 8). This supports potential hydrogen bonds between the substrate
(lactide) and the ligand, and highlights the importance of hydrogen bond donors in the catalytic
pocket. We find these topographic steric maps a complementary tool that supports the previously
discussed NCI surfaces.
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Figure 7: Potential energy surface (PES) corresponding to first L-lactide insertion (initiation step).
Data available here, DOI: 10.14469/hpc/3779.
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I(c) VI(t)-TS
Figure 8: Topographic steric map of I(c) (left) and VI(t) (right) showing the position of the NH
bond donor in the catalytic pocket.
Propagation and stereoselectivity. In order to perceive the observed stereoselectivity, the
reaction of VIII with a second lactide molecule has been considered with both L- and D-lactide
molecules alternatively (Figure 9). As previously observed in the initiation step, the lactide
“docking” on the top of the catalyst has been found energetically favorable (∆G298 = -9.7 kcal/mol
and ∆G298 = -8.0 kcal/mol for both D- and L-lactide, respectively). As highlighted in the NCI
surfaces, similar hydrogen bonds can be observed between the oxygen atom of the lactide carbonyl
and the NH moieties (Figure S34-S35). For both D- and L-lactide, the rate determining step was
found to be the ring opening (as previously observed during the initiation) with an energy barrier
difference of ∼2 kcal/mol in favor of a D-lactide over L-lactide insertion. This is in accordance
with the formation of a highly heterotactic PLA as experimentally observed (Pr ∼ 0.9).46
Interestingly, XIII(D)-TS also features a lower FDE than XIII(L)-TS (FDE = 3.1 kcal/mol for
XIII(D)-TS vs FDE = 7.0 kcal/mol for XIII(L)-TS). A single point analysis of the TS has to be
considered cautiously and the true origin of the activation energy will require analysis along the
reaction pathway, for example using a distortion/interaction-activation strain model.58
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Figure 9: PES showing second insertion of a lactide monomer (red = L-lactide, blue = D-lactide)
after initial insertion of L-lactide as per initiation step in Figure 7 (“twisted” conformation). Data
available here, DOI: 10.14469/hpc/3799.
Conclusion
This new family of aluminium catam complexes combines both high activity at room
temperature and high heteroselectivity for rac-latide ROP. Structural characterisations of these
aluminium complexes show that the NH moieties of the ligand can act as hydrogen bond donors.
Mechanistic investigations establish that methylation of the NH moieties inhibits the catalyst
activity at room temperature. Preliminary kinetic studies indicate that substituting the NH moieties
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by ND moieties lead to a kinetic isotope effect which could be attributed to monomer binding via
the NH moieties. Finally, computational studies reveal that the NH hydrogen bond donors are well-
positioned in the catalytic pocket to interact with the reactive species (lactide, growing polymer)
and to form hydrogen bonds, as highlighted on the NCI surfaces. Overall, structural
characterisation of the catalysts, mechanistic, kinetic and computational studies highlight the
importance of the NH moieties in the ligand to act as hydrogen bond donors and form beneficial
hydrogen bonds during the polymerisation. Ligand design is currently under investigation to
further exploit these non-covalent interactions to afford highly isoselective and highly active
aluminium catalysts, which still remains a challenge in the field.
Supporting Information. The following files are available free of charge.
NMR spectra, kinetic data, details of DFT calculations included in a PDF file.
FAIR Data59, 60 and web-enhanced tables are available from DOI: 10.14469/hpc/3716, as per
funding council guidelines.
Corresponding Author
* Charles Romain, [email protected]
Author Contributions
The manuscript was written through contributions of all authors.
ACKNOWLEDGMENT
The authors thank ICL HPC for the computing resources, Peter Haycock for the DOSY NMR
spectra and Stephen Boyer (London Metropolitan University) for the elemental analysis. RS thanks
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Academy of Finland, Harry Elvings Legat and Svenska tekniska vetenskapsakademien i Finland
for funding. CR thanks Imperial College London for his Junior Research Fellowship and Prof.
George Britovsek for his mentorship.
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