Monomeric Ti(IV) homopiperazine complexes and their exploitation for the ring opening polymerisation of rac-lactide

Background The area of biodegradable/sustainable polymers is one of increasing importance in the 21st Century due to their positive environmental characteristics. Lewis acidic metal centres are currently one of the most popular choices for the initiator for the polymerisation. Thus, in this paper we report the synthesis and characterisation of a series of monometallic homopiperazine Ti(IV) complexes where we have systematically varied the sterics of the phenol moieties. Results When the ortho substituent of the ligand is either a Me, tBu or amyl then the β-cis isomer is isolated exclusively in the solid-state. Nevertheless, in solution multiple isomers are clearly observed from analysis of the NMR spectra. However, when the ortho substituent is an H-atom then the trans-isomer is formed in the solid-state and solely in solution. The complexes have been screened for the polymerisation of rac-lactide in solution and under the industrially preferred melt conditions. Narrow molecular weight material (PDI 1.07 – 1.23) is formed under melt conditions with controlled molecular weights. Conclusions Six new Ti(IV) complexes are presented which are highly active for the polymerisation. In all cases atactic polymer is prepared with predictable molecular weight control. This shows the potential applicability of Ti(IV) to initiate the polymerisations.


Background
As part of our on-going studies into the chemistry of group 4 metals and homo/piperazine derived salan ligands [1][2][3] in this paper we report the synthesis and characterisation of series of monometallic complexes based on the homopiperazine backbone. This ligand family has also been applied to Fe(III) [4,5], Cu(II) [6], Ni(II) [6] and Mo(VI) [7] metal centres. Typically these are either monomeric or dimeric structures in the solid-state. These 7-membered ring ligands are underrepresented in the literature compared to their 6membered brothers or their linear amine bis(phenolate) cousins [8][9][10][11][12][13]. To re-address this imbalance we have previously reported the formation of Ti 2 (O i Pr) 6 L or monometallic Zr/Hf(O i Pr) 2 L species (containing homopiperazine salan ligands) where, in the monometallic examples, the O i Pr moieties are trans to one another [3]. Utilising the piperazine derived salan ligands with Zr(IV) and Hf(IV) starting materials leads to unpredictable reactions with no rationale control over the product formed [3]. These complexes have been shown to be effective initiators for the ring opening polymerisation (ROP) of cyclic esters [2,3]. Moreover, we have prepared Al(III) complexes of homopiperazine salan ligands for co-polymerisations of cyclic esters [1]. The rich and unexplored chemistry of this ligand set motivated us to prepare monometallic Ti(IV) complexes for the controlled ROP of rac-lactide. The driving force for this work also lies in the attractive properties of the final polymer polylactide (PLA) itself, such as biodegradability, it is produced from annually renewable resources and the fact that the polymer is also biocompatible [14]. These facets have spear-headed research in this area and metals such as Ca(II) [15,16], Mg(II) [17][18][19][20], Zn(II) [21][22][23][24][25][26][27], Al(III) [28][29][30][31][32][33][34][35][36], Bi(III) [37], Ti(IV)/Zr(IV) [38][39][40] and metal-free systems [41][42][43] have all proved excellent choices in the literature. The controlled polymerisation of rac-lactide can lead to either atactic, heterotactic or isotactic PLA the later possessing a significantly higher melting temperature. There is an exigent desire to prepare and characterise new initiators for the ROP of lactide to enhance the already impressive properties of the material. A selection of complexes for the polymerisation of rac-lactide is shown in Figure 1. One of the earliest examples of the ROP of rac-lactide was by Spassky and co-workers [33], they produced isotactically enriched PLA with an Aluminium Schiff base complex. Then followed seminal studies on Zn-BDI complexes [17], in solution with a monomer: initiator ratio of 200:1 at 20°C heterotactic PLA P r = 0.90 was produced. There is a desire to move towards melt polymerisations, in the absence of solvent. One of the first examples of this approach was the work of Feijen [35], who produced highly isotactically enriched PLA from raclactide at 130°C (monomer:initiator 200:1), however to achieve high conversions 48 hours was required. Davidson has shown that it is possible to produce heterotactically (P r = 0.90) enriched PLA in the melt with a group 4 amine tris(phenolate) complex (monomer:initiator 300:1), near quantitative conversion was achieved after 10 minutes [44].

Complex preparation
Literature preparation methods were utilised to prepare the homopiperazine salan ligands, (1-6)H 2 [3,45]. The complexes were prepared by a 1:1 reaction of the salan with Ti(O i Pr) 4 at 80°C, this was carried out under a flow of Ar to facilitate the removal of isopropanol to drive the reaction to the formation of the 1:1 complex. The additional heating (80°C) allowed the homopiperazine ring backbone to adopt the thermodynamically unfavourable boat type configuration and furthermore coordinate both phenols and nitrogen centres to a single titanium metal centre, Scheme 1. These complexes were characterised by elemental analysis, 1 H, 13 C{ 1 H} NMR spectroscopy and where possible single crystal X-ray diffraction.
The solid-state structures Ti(2,4-6)(O i Pr) 2 have been determined by single crystal X-ray diffraction, and have yielded monometallic complexes with the titanium metal centres adopting a pseudo octahedral configuration. The structure obtained for Ti(2)(O i Pr) 2 is given as a representative example ( Figure 2). Ti (2,4,5)(O i Pr) 2 adopt a β-cis configuration in the solid-state, this is in contrast to the Zr(IV)/Hf(IV) analogues which formed trans complexes. However, with less steric bulk in the ortho-phenol position a pseudo trans-octahedral titanium complex supported by a homopiperazine salan ligand, Ti(6)(O i Pr) 2 ( Figure 3), was isolated.
Selected bond lengths (Å) and angles (°) are given in Table 1 for the crystallographically characterised titanium homopiperazine complexes. Those complexes which adopted a β-cis configuration {Ti(2,4-6)(O i Pr) 2 } revealed similar bond lengths and angles. There was no significant difference in the isopropoxide metal (Ti1-O1, Ti1-O2) bond lengths, but phenoxy-metal bond lengths (Ti1-O3, Ti1-O4) were significantly different with the phenoxy trans to an isopropoxide exhibiting a longer bond length. The two Ti-N bonds are different with Ti-N trans to an isopropoxide being the longer distance. The complexes adopted a distorted octahedral conformation, which is demonstrated by the deviation of the titanium angles from 90°or 180°, for cis or trans angles respectively. A high degree of variation from the idealistic 90°angle was observed between N1-Ti1-N2, giving angles between 67.90(13) -68.08(7)°.
The less sterically hindered salan complex with hydrogen atoms at the ortho positions adopted a distorted trans-octahedral structural configuration {Ti(6)(O i Pr) 2 } ( Figure 3). The two phenoxy-titanium bonds (Ti1-O1, Ti1-O2) are equivalent in length, additionally the two nitrogen-titanium bonds (Ti1-N1, Ti1-N2) are equivalent in length. This is indicative of the structures symmetrical nature. Similar to β-cis configurations the trans-octahedral structure deviates from an ideal octahedral environment.
The solution-state NMR spectra for the monometallic titanium piperazine salan complexes Ti (1)(2)(3)(4)(5)  isopropoxide -CH 3 resonances were located at 0.40 ppm and 1.19 ppm (presumably the β-cis isomer) and a broad resonance was further observed between 0.45 -1.55 ppm. The fluxional nature is supported by variable temperature NMR spectroscopy (233 K) where the resonances become much more defined at lower temperatures. These complexes can adopt the α-cis, β-cis, and trans octahedral conformations. Although the Δ and Λ forms of α-cis and β-cis conformations are possible they are indistinguishable by conventional NMR spectroscopy ( Figure 4) [46]. It should be noted that although three octahedral conformations are present the orientation of the homopiperazine ring can further complicate the NMR spectra.
The more sterically hindered complexes Ti(3-5) (O i Pr) 2 , with respect to the ortho-phenoxy positions, primarily adopted two conformations. The two conformations can be observed in their NMR spectra. For example for Ti(3)(O i Pr) 2 the isopropoxide -CH 3 region shows doublets at 0.39 ppm, 0.98 ppm and 1.01 ppm which are related to one conformation. The analogous resonances are present from the other conformation at 0.55 ppm, 0.72 ppm, 0.94 ppm, and 0.97 ppm (each a 3H integral) respectively. The two species were present in an approximate 1:0.9 ratio. The same can be observed in the aromatic region where resonances at 6.88 ppm, and 7.25 ppm were attributed to the slightly dominant conformation. The 1 H NMR resonances are relatively well defined for each conformation at room temperature, it was speculated that the increased steric demands of the ligands reduce fluxionality within the complex when compared to Ti(1-2)(O i Pr) 2 .
thus consistent with a trans octahedral geometry being formed exclusively. This is further supported by the presence of two isopropoxide septets at 3.84 ppm and 4.82 ppm.

Polymerisation studies
The isolated Ti(1-6)(O i Pr) 2 complexes were trialled for the ROP of rac-lactide in toluene (10 ml) at 80°C at a 100:1 [rac-lactide]:[Initiator] ratio (Table 2). Limited activity was observed for this initiator series under these conditions typically achieving low conversions after 24 h. The molecular weights were consistent with one PLA chain per metal; additionally PDI values were low indicating a more controlled polymerisation system than their bimetallic counterparts [2]. The monometallic system is stable at 80°C therefore it was assumed the monometallic species were initiating the polymerisation reaction. Where the initiators were active enough to obtain reliable P r values a slight isotactic bias was observed.
Ti(1-6)(O i Pr) 2 titanium salan complexes were trialled for the ROP of rac-lactide without solvent at 130°C at a 300:1 [rac-lactide]:[Initiator] ratio (Table 3). Under solvent free conditions these initiators typically achieved 41-60% conversion after 24 h. Despite the presence of two potentially initiating isopropoxide groups per metal the PDI values remained low (PDI < 1.25) at the elevated temperature. The defined structure permits the formation of controlled PLA chains but the lack of flexibility within the molecules causes the initiators to be hindered thus leading to reduced activity. Under melt conditions Ti(1-6)(O i Pr) 2 complexes produced PLA with a slight heterotactic bias (P r = 0.51 -0.63). The steric effects do not seem to significantly alter the polymerisation, with the more bulky amyl substituted complex being more active than the sterically unhindered Ti(6)(O i Pr) 2 complex.

Conclusions
In conclusion a series of six new Ti(IV) complexes have been prepared based on a homopiperazine salan derived ligand. In solution a multitude of species are formed.
However, in the solid-state the β-cis and trans forms were observed, depending on the steric requirement of the ligand. All complexes were active for the ROP of rac-LA in solution and under the industrially preferred melt conditions.

Methods
For the preparation and characterisation of metal complexes, all reactions and manipulations were performed under an inert atmosphere of argon using standard Schlenk or glovebox techniques. rac-lactide (Aldrich) was recrystallised from toluene and sublimed twice prior to  (14) 19.3720 (7) 10.9250 (7) 14.0530 (2

Polymerisation
For solvent-free polymerisations the monomer:initiator ratio employed was 300:1 at a temperature of 130°C, in all cases 1.0 g of rac-lactide was used. After the reaction time methanol (20 ml) was added to quench the reaction and the resulting solid was dissolved in dichloromethane. The solvents were removed in-vacuo and the resulting solid washed with methanol (3 × 50 ml) to remove any unreacted monomer. For solution polymerisations a monomer:initiator ratio of 100:1 was used. In all cases 1.0 g of lactide and the appropriate amount of initiator were dissolved in toluene (10 ml) these were placed in a preheated oil bath and heated for the desired amount of time.
For the melt polymerisation 1.0 g of lactide was used in the absence of solvent. The reaction was quenched by the addition of methanol (20 ml). 1 H NMR spectroscopy (CDCl 3 ) and GPC (THF) were used to determine tacticity and molecular weights (M n and M w ) of the polymers produced; P r/m (the probability of heterotactic/isotactic linkages) were determined by analysis of the methine region of the homonuclear decoupled 1 H NMR spectra [17]. Gel Permeation Chromatography (GPC) analyses were performed on a Polymer Laboratories PL-GPC 50 integrated system using a PLgel 5 μm MIXED-D 300 × 7.5 mm column at 35°C, THF solvent (flow rate 1.0 ml/min). The polydispersity index (PDI) was determined from M w /M n where M n is the number average molecular weight and M w the weight average molecular weight. The polymers were referenced to polystyrene standards.

Single crystal diffraction
All data were collected on a Nonius kappa CCD diffractometer with MoKα radiation, λ = 0.71073 Å, see Table 4. T = 150(2) K throughout and all structures were solved by direct methods and refined on F 2 data using the SHELXL-97 suite of programs [47]. The data as cif format are given in supporting information as Additional file 1. Hydrogen atoms, were included in idealised positions and refined using the riding model. Refinements were generally straightforward with the following exceptions and points of note. Ti(4)(O i Pr) 2 despite copious recrystallisation efforts the R int was higher than desirable. Ti(5)(O i Pr) 2 one isopropoxide is disordered over two positions in a 60:40 ratio and despite copious recrystallisation efforts the R int was higher than desirable. Ti(6)(O i Pr) 2 one isopropoxide is disordered over two positions in a 60:40 ratio, the CH 3 groups of one tBu are disordered over two positions in a 60:40 ratio and one toluene is disordered over two positions in a 50:50, and despite copious recrystallisation efforts the R int was higher than desirable.

Additional file
Additional file 1: Crystallographic data. Crystallographic data in CIF format for complexes CCDC Nos: 951134-951137.