1

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.

2

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,

3

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.

4

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

5

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

6

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).

8

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)

-

-

-

-

-

-

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

9

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

10

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. %

11

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

12

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

13

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

14

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

15

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.

16

Figure 7: Potential energy surface (PES) corresponding to first L-lactide insertion (initiation step).

Data available here, DOI: 10.14469/hpc/3779.

17

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

18

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

19

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, c.romain@ic.ac.uk

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

20

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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