Main-chain chiral copoly(2-oxazoline)s

Abstract

(Chiral) poly(2-oxazoline)s are regarded as pseudo-polypeptides, however, not much is known about their secondary structure formation. Recently we reported that chiral homopolymers based on R- and S-2-butyl-4-ethyl-2-oxazoline (BuEtOx) monomers form flexible dynamic helices in solution (Soft Matter, 2010, 6, 994–1003) and a chiral crystalline structure in the solid state (Macromolecules, 2010, 43, 4654–4659). In the current work we addressed the chiral structure formation of main-chain chiral copoly(2-oxazoline)s with controlled ratio of S-BuEtOx and R-BuEtOx. No chiral amplification was found in solution or in the solid state, clearly indicating that the polymers adopt a dynamic helical structure that is easily disrupted by incorporation of the second monomer. Nonetheless, the properties of these main-chain chiral copoly(2-oxazoline)s, such as the optical rotation, solubility and crystallinity, can be tuned by controlling the enantiomeric excess (ee).

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Introduction

Chiral helical polymers can be divided into two groups: helical polymers with high helix inversion barriers, the so-called static helical polymers, and helical polymers with low helix inversion barriers, known as dynamic helical polymers.^1–4 Static helical polymers have in general bulky side groups that lock the preferred handed secondary structure during polymerization under kinetic control, dynamic helical polymers usually have a chiral pendant group.⁴ Chiral amplification in polymer systems has been first reported for polyisocyanates by Green et al.^1,5 A copolymer of achiral and chiral isocyanates was demonstrated to form a helical structure with only a small amount of chiral monomer, the so-called “sergeant and soldiers” effect.^1,3,5 In addition, a small enantiomeric excess (ee) in a polymer chain comprising both isocyanate enantiomers resulted in an almost perfect one-handed helical structure, which is called the “majority rules principle”.^4–6

Poly(2-oxazoline)s^7–9 with a substituent on the 4^th or 5^th position are main-chain chiral polymers^10–14 that, according to a model published by Oh et al.,¹⁵ are expected to form a helical structure. Our previous investigations by combined small angle neutron scattering (SANS) and circular dichroism (CD) on poly(R-2-butyl-4-ethyl-2-oxazoline) (p-R-BuEtOx) and p-S-BuEtOx homopolymers revealed that these polymers form a flexible and dynamic secondary structure in solution, in which parts of the polymer chain form a defined secondary structure while other parts are present as a random coil.¹⁶ Furthermore, differential scanning calorimetry (DSC) together with CD measurements of a polymer film revealed that the crystalline parts of the polymer are organized in a chiral structure in the solid state.¹⁷

In the current work we report the copolymerization of R-BuEtOx or S-BuEtOx with RS-BuEtOx (Fig. 1) to investigate the secondary structure formation in main-chain chiral copoly(2-oxazoline)s, which can be regarded as pseudo-polypeptides, in further detail. The main objectives are the determination of the polymer properties, both in solution and in the solid state, as a function of ee as well as whether these polymers follow the majority rules principle. Therefore the ee of the random copolymers consisting of R-BuEtOx and S-BuEtOx was systematically varied. The influence of the ee on the copolymer solubility will be addressed based on turbidity measurements. Optical rotation and CD measurements were performed in solution to investigate the influence of the ee on the chiroptical properties. Finally, the effect of the ee on the solid state organisation of the copolymers will be discussed based on DSC and CD measurements.

Fig. 1 Reaction scheme of the copolymerization of S-BuEtOx with RS-BuEtOx initiated with methyl tosylate (MeOTs).

Experimental

The synthesis of p-R-BuEtOx, p-S-BuEtOx and p-RS-BuEtOx homopolymers was described in a recently published paper.¹⁶ The copolymers were prepared in a similar way by weighing in the desired amount of R-BuEtOx or S-BuEtOx together with RS-BuEtOx. A typical polymerization procedure is as follows: for the R-rich polymers a mixture of R-BuEtOx and RS-BuEtOx with an initial monomer concentration of 4 M in dichloromethane and a monomer to initiator ([M]/[I]; I = methyl tosylate) ratio of 60 was used. The S-rich polymers were prepared by mixing S-BuEtOx with RS-BuEtOx with an initial monomer concentration of 4.5 M in acetonitrile and a [M]/[I] ratio of 50. The polymerization mixtures were heated to 180 °C under microwave irradiation for 60 min. After cooling the mixtures to <40 °C, the polymerizations were quenched by the addition of water. The polymers were dried, precipitated from tetrahydrofuran into demineralized water and again thoroughly dried at 40 °C under reduced pressure before further characterization.

Size exclusion chromatography (SEC) was measured on a Shimadzu system with a LC-10AD pump, a RID-10A refractive index detector, a system controller SCL-10A, degasser DGU-14A and a CTO-10A column oven and two PSS GRAM 10 µm, 8 mm × 300 mm, 1000/30 Å columns using N,N-dimethylacetamide (DMA) with ∼2 g L⁻¹LiCl as the eluent at a flow rate of 0.5 mL min⁻¹ and the column oven set to 50 °C. A polystyrene calibration was used to calculate molar mass values.

Solubility tests were performed using the Crystal 16 from Avantium Technologies at a concentration of 5 mg mL⁻¹. The transmittance was measured at a temperature range from −15 °C to 65 °C using methanol, ethanol, n-butanol, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, n-heptane and cyclohexane as solvent.

Optical rotation at the Na-D line was measured with a sample concentration of 30 mg mL⁻¹ in chloroform at room temperature with a polarimeter using a quartz cell with a path length of 10 cm.

UV and CD absorption spectra were measured simultaneously on a Jasco J815 spectropolarimeter equipped with a PTC-348WI temperature controller for temperatures ranging from −10 to 110 °C. Measurements were performed in a 0.1 cm quartz cell using sample concentrations of 0.25 mg mL⁻¹. The following scanning conditions were used: 50 nm min⁻¹ scanning rate; 1 nm bandwidth; 0.1 nm data pitch; 0.5 s response time; and 10 accumulations.

CD spectra in the solid state were measured on a Jasco J815 spectropolarimeter equipped with a Linkam temperature controller. The samples were spin coated from chloroform (20 mg mL⁻¹) on a quartz slide for 2 minutes with 2000 rpm and annealed at 140 °C for 24 h after measuring the as spin coated sample. The following scanning conditions were used: 50 nm min⁻¹ scanning rate; 1 nm bandwidth; 0.1 nm data pitch; 0.5 s response time; and 10 accumulations.

Thermal transitions were determined on a DSC 204 F1 Phoenix by Netsch under a nitrogen atmosphere with cooling rates of 40 °C min ⁻¹ and heating rates of 20 °C min⁻¹.

Results and discussion

The enantiopure and racemic BuEtOx monomers were (co)polymerized under previously optimized microwave assisted conditions, namely 60 minutes at 180 °C, resulting in more than 80% conversion for all copolymers.^16,18–21Size exclusion chromatography (SEC) revealed the formation of relatively well-defined copolymers with polydispersity indices ranging from 1.24 to 1.43 (Table 1). Fig. 2a shows representative SEC traces demonstrating the monomodality of the molar mass distributions. The observed differences in the number average molar mass (M_n) of the copolymers are due to small differences in the actual monomer to initiator ([M]/[I]) ratios as well as variations in the extent of chain-transfer side reactions caused by protic impurities such as water. The PDI values of the R-rich copolymers are somewhat higher, most likely due to the use of dichloromethane instead of acetonitrile, which was used for the S-rich polymers, as polymerization solvent. Dichloromethane can act as a very poor initiator leading to broadening of the molar mass distribution at higher retention times due to slow initiation (Fig. 2a). Nonetheless, in the second part of this project, dichloromethane was utilized as polymerization solvent since it is a better solvent for the p-BuEtOx polymers resulting in higher monomer conversions (∼90%) compared to acetonitrile (∼80%).

Table 1 SEC results and optical rotation of the synthesized (co)polymers with varying ee^a

ee R-BuEtOx (%)	M n/g mol^−1	PDI	[α]D^RT^b/10^−1 deg cm^2 g^−1
a Polystyrene calibration. b Measured in chloroform with a concentration of 30 mg mL^−1. c Used for DSC measurements. d Used for CD measurements. e Not measured.
100	4100^c	1.24^c	−26
	6090^d	1.29^d
95	4960	1.37	−22
90	5390	1.37	−20
85	5670	1.43	−16
80	4490	1.31	−15
75	7810	1.37	n.m.^e
70	5670	1.39	−11
65	5630	1.43	n.m.^e
60	5820	1.38	−6.9
55	5580	1.36	−2.7
50	5100	1.25	−0.2
33	5060	1.25	+8.2
17	4960	1.27	+16
0	4950	1.27	+26

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Fig. 2 (a) Representative SEC traces of the copolymers synthesized in dichloromethane (95% R-BuEtOx) and acetonitrile (83% S-BuEtOx). (b) Optical rotation as a function of the amount of R-BuEtOx present in the copolymer. The solid line is a linear fit through the data.

Solution properties of the BuEtOx copolymers

The solution properties of the synthesized BuEtOx copolymers with varying ee were investigated by polarimetry, turbidimetry and CD. The optical rotation of the copolymers was determined in chloroform solution and was found to linearly decrease with theoretical ee from [α]_D^RT = +26 × 10⁻¹ deg cm² g⁻¹ (c 30 in CHCl₃) for p-S-BuEtOx to [α]_D^RT = −26 × 10⁻¹ deg cm² g⁻¹ (c 30 in CHCl₃) for p-R-BuEtOx and [α]_D^RT = 0 × 10⁻¹ deg cm² g⁻¹ (c 30 in CHCl₃) for the racemic polymer (p-RS-BuEtOx) (Fig. 2b). This linear dependence in optical rotation with ee indirectly proves that the copolymers have indeed the desired ee.

The solubility of the homopolymers as well as the copolymers was investigated by turbidity measurements in a range of solvents at a concentration of 5 mg mL⁻¹ (Table 2). Both homo-polymers are only soluble in tetrahydrofuran (THF) and n-butanol, whereby heating was required to disrupt the crystalline fractions. When the ee decreased to 95%, the solubility did not significantly change. However, when the ee was decreased to 90%, the polymer became well-soluble in all investigated solvents indicating that the secondary structure is interrupted with the addition of the second enantiomer resulting in improved solubility. As such, the solubility of the main-chain chiral poly(2-oxazoline)s can be enhanced maintaining their chirality to a large extent (90% ee).

Table 2 Solubility of the (co)polymers measured at 5 mg mL⁻¹ and the dielectric constants and dipole moments of the solvents

Solvent	100% ee	95% ee	90% ee	Dielectric constant^a	Dipole moment^a
a Taken from the CRC Handbook of Chemistry and Physics, 86^th edition.
n-Heptane	Insoluble	Insoluble	Soluble	1.92	∼0
Cyclohexane	Insoluble	Insoluble	Soluble	2.02	∼0
Tetrahydrofuran	Soluble	Soluble	Soluble	7.52	1.75
n-Butanol	Soluble	Soluble	Soluble	17.84	1.66
Ethanol	Insoluble	Insoluble	Soluble	25.3	1.69
Methanol	Insoluble	Insoluble	Soluble	33.0	1.70
Acetonitrile	Insoluble	Insoluble	Soluble	36.64	3.92
N,N-Dimethylformamide	Insoluble	Insoluble	Soluble	38.25	3.82

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The chiroptical properties of the copolymers were further investigated by CD (Fig. 3a and b). The double Cotton effect in CD retains the same shape and decreases in intensity with decreasing ee (Fig. 3a). The Cotton effects disappear for the racemic p-RS-BuEtOx and are opposite in sign for (co)polymers with an ee of R-BuEtOx compared to the polymers with an ee of S-BuEtOx. Like the optical rotation, also the Cotton effects decrease linearly with the reduction in ee (Fig. 3b). These results demonstrate a decrease in persistence length of the chiral regimes in the copolymers with decreasing ee and the absence of the majority rules principle in solution for which an S-shaped relation of both optical rotation and the Cotton effects would be expected as a function of ee.^5,22,23

Fig. 3 (a) CD spectra of the chiral poly(2-oxazoline)s with different ee. The legend indicates the amount of R-BuEtOx present in the polymer. (b) CD maxima as a function of the amount of R-BuEtOx present in the copolymer. Solid lines are linear fits through the data.

Solid state properties of the BuEtOx copolymers

The solid state properties of the main-chain chiral BuEtOx copolymers were studied by differential scanning calorimetry (DSC) and CD of thin polymer films to investigate the effect of ee on crystallization and the formation of ordered chiral structures. In the first heating run (Table 3 and Fig. 4a), only the enantiopure polymers and the copolymers with an ee of 90% or higher revealed a single or double melting peak (T_m1 and T_m2), indicating that they are semi-crystalline. The difference in enthalpy (ΔH_m) is small between p-R-BuEtOx and the copolymer with an ee of 95% of p-R-BuEtOx. However, when the ee decreases to 90%, ΔH_m decreases to approximately 1/3 of the crystallinity of the enantiopure polymer and no crystallinity is observed for the copolymers with an ee of 85% or less. In fact, this decrease in crystallinity explains the observed increase in solubility as discussed in the previous part, i.e. there is no competition between crystallization and solvation of the polymer chains, which is similar to chiral vinyl polymers for which the solubility decreases with increasing isotacticity due to the higher crystallinity.⁵

Table 3 Thermal properties of the investigated polymers measured by DSC^a

R-BuEtOx (%)	First heating run			Second heating run		Third heating run^b
	T m1/°C	T m2/°C	ΔHm^c/J g^−1	T g ^d/°C	ΔCp/J g^−1 K^−1	T m1/°C	T m2/°C	ΔHm^c/J g^−1
a Heating rate of 20 K min^−1. b After 24 h annealing at 140 °C. c Cumulative ΔHm of both observed melting transitions. d Midpoint of the observed transition.
100	—	220	31	52	0.36	197	221	39
95	—	205	27	53	0.27	188	206	39
90	184	198	8	58	0.30	184	200	37
80	—	—	—	46	0.36	178	—	15
75	—	—	—	41	0.19	—	—	—
70	—	—	—	49	0.29	—	—	—
65	—	—	—	57	0.11	—	—	—
60	—	—	—	54	0.24	—	—	—
55	—	—	—	55	0.22	—	—	—
50	—	—		45	0.28	—	—	—
33	—	—	—	53	0.30	—	—	—
17	—	—	—	54	0.25	178	—	22
0	—	218	36	50	0.33	193	217	37

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Fig. 4 DSC traces of the enantiopure polymers and copolymers (a) first heating run (20 °C min⁻¹), (b) second heating run (20 °C min⁻¹) and (c) after annealing for 24 h at 140 °C (20 °C min⁻¹). The legend indicates the amount of R-BuEtOx present in the polymer. (d) Melting enthalpy and melt temperatures as a function of the enantiomeric excess after annealing the polymers.

In the second heating run (Table 3 and Fig. 4b), a glass transition temperature (T_g) was observed around 50 °C with a heat capacity (ΔC_p) of approximately 0.3 J (g⁻¹ K⁻¹) for all investigated BuEtOx copolymers. The crystals initially present in the copolymers with 95% or 90% ee R-BuEtOx are not capable of crystallizing again from the melt or from the glassy state after melting during the DSC measurement and only the enantiopure polymer revealed a T_m in the second heating run.

The polymer samples were subsequently annealed to induce crystallization. After annealing the polymers for 24 h at 140 °C, the copolymers with an ee up to 80% partially crystallized as indicated by the melting transitions (Table 3 and Fig. 4c). Therefore, it can be concluded that these copolymers can crystallize when they are heated for some time above the T_g, which increases the chain mobility allowing reorganization of the chains.

Upon annealing a second melting peak at a lower temperature appeared for the enantiopure polymer and the copolymer with 95% R-BuEtOx and the first melting peak in the copolymer containing 90% R-BuEtOx increased (Fig. 4c). It appeared that these crystals partially melt-recrystallize into more perfect crystals resulting in the second melting peak at a higher temperature.¹⁶ Upon annealing it was also possible to induce crystal formation in copolymers containing 85%, 80% and 17% R-BuEtOx, while these polymers were initially amorphous after polymerization and purification. However, for these polymers no melt-recrystallization into more perfect crystals is observed. Since the ratio between ΔH_m1 and ΔH_m2 decreases with the decrease in ee, it seems that the extent of imperfect crystals increases and the amount of crystals that recrystallize into more perfect crystals during melting is reduced. With the decrease in ee, the total ΔH_m and T_m are decreased (Fig. 4d), indicating a reduction in the amount and quality of the crystals formed. Therefore, it can be concluded that the chiral crystalline structure is interrupted by the incorporation of the other enantiomer. A similar behavior was observed for polypropylene (PP) with a decrease in tacticity.²⁴ The crystalline structures were further investigated by CD of the polymer films.

The CD measurements of spin coated polymer films revealed similar Cotton effects as in solution except for the peak maxima being slightly shifted to higher wavelengths (Fig. 5a). Since the strength of the Cotton effects is strongly influenced by the film thickness, the ratio between the maximum Cotton effects before and after annealing will be compared instead of the absolute intensities (Fig. 5b). Annealing the enantiopure polymer films for 24 h at 140 °C resulted in a change of the chiral structure, since the ratio between the maximum Cotton effects significantly changed. Before annealing both Cotton effects have approximately the same strength, while after annealing the Cotton effect at ∼202 nm is strongly enhanced while the Cotton effect at ∼218 nm remains small. The ordered chiral structure formed during annealing is similar to the chiral structure present in the crystals formed during cold crystallization as observed previously for the homopolymers.¹⁷ This observed change in chiral structure in the solid state is unusual, since in most chiral polymers the Cotton effects only increase in intensity upon annealing, indicating an increase in persistence length of the chiral structure. This was also observed for the copolymers containing 90% or 95% R-BuEtOx, in which an increase in Cotton effects is observed without a change in the ratio between the maximum Cotton effects after annealing (Fig. 5b). The maximum Cotton effects for the copolymers containing 80% or 17% R-BuEtOx hardly increased upon annealing (not shown), even though a melting peak is observed after annealing these copolymers. The formation of less perfect crystals, as observed with DSC, is probably the reason why the Cotton effects of these copolymers do not strongly increase upon annealing. When the ee is further decreased, no change in CD spectra could be observed after annealing since these polymers are amorphous and, thus, no chiral crystals are formed.

Fig. 5 Normalized (by setting the maximum UV absorption at 1 A) (a) CD spectra of the (co)polymers after annealing for 24 h at 140 °C. The legend indicates the amount of R-BuEtOx present in the (co)polymer. (b) Ratio of the maximum Cotton effects before and after annealing for 24 h at 140 °C.

Conclusion

Well-defined BuEtOx copolymers with controlled ee ranging from pure S-BuEtOx to pure R-BuEtOx were successfully prepared with polydispersity indices ranging from 1.24 to 1.43. The linear dependence of the optical rotation and the Cotton effects on the ee demonstrates the absence of the majority rules principle in solution indicating that these main-chain chiral poly(2-oxazoline)s adopt a dynamic flexible secondary structure, presumably due to the high flexibility of the polymer chains and the absence of stabilizing interactions within the formed secondary structures.

The DSC results indicate that, upon annealing, polymers with an ee of 80% or higher can form crystalline structures. The amount and quality of the crystals depend on the ee and decrease with decreasing ee, indicating that the crystal structure becomes less perfect by the incorporation of the second monomer. This decreased crystallinity also explains the better solubility of the copolymers with decreasing ee. CD measurements revealed that the crystals have an ordered chiral structure and confirmed that the incorporation of the second enantiomer disrupts the crystalline chiral structure.

All together, it is demonstrated that the optical activity, solubility and thermal properties of the BuEtOx main-chain chiral copolymers can be controlled by the ee. As such, these results represent an important step in further understanding the secondary structure formation of main-chain chiral poly(2-oxazoline)s, which can be regarded as pseudo-polypeptides, and will be important for the design of related poly(2-oxazoline) structures with more defined secondary structures.

Acknowledgements

The authors thank the Dutch Polymer Institute (DPI) for financial support.

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