Macromolecules with programmable shape, size, and chemistry

Significance

Tuning shape, size, and chemical composition elicits a way to mediate function. In soft materials, the establishment of these structure–function relationships has been hampered by the inability to independently control the shape, size, and composition of macromolecules. Here, we establish a synthetic methodology combining a computer-controlled process and two controlled polymerizations to yield macromolecules with any monotonic axisymmetric shape up to 300 nm in size. The methodology has a simple and scalable setup to yield gram quantities of macromolecules from commercially available materials. This approach provides a unique material platform to study the impact of shape, size, and composition of macromolecules.

Abstract

Shape, size, and composition are the most fundamental design features, enabling highly complex functionalities. Despite recent advances, the independent control of shape, size, and chemistry of macromolecules remains a synthetic challenge. We report a scalable methodology to produce large, well-defined macromolecules with programmable shape, size, and chemistry that combines reactor engineering principles and controlled polymerizations. Specifically, bottlebrush polymers with conical, ellipsoidal, and concave architectures are synthesized using two orthogonal polymerizations. The chemical versatility is highlighted by the synthesis of a compositional asymmetric cone. The strong agreement between predictions and experiments validates the precision that this methodology offers.

Tuning the shape, size, and chemical composition is a way to mediate the function of molecules to biological structures (1). An example eliciting this can be seen in the shape of viruses (e.g., conical shape of HIV-1 capsid or the bullet shape of a rabies-related virus), in which the virulence is dictated by the shape of the pathogen, or in antibodies where complementary antigen targets in specific locations are required for activity (1–4). Given the importance of controlling the function of materials, scientists have developed various synthetic strategies to control the shape, size, and chemistry of nanomaterials. Most notably, advancements in colloidal particle synthesis have enabled the tuning of physical, electrical, and chemical properties of inorganic nanomaterials by varying their shape, size, and composition (5–7). Today, these hard particles find diverse applications varying from quantum dots for portable displays to biological systems for imaging, detecting, and treating diseases (1, 8). In soft materials the independent control of shape, size, and composition of macromolecules remains nontrivial, which overall limits our ability to realize and mediate advanced functionalities (9).

Dendrimers and hyperbranched polymers have been synthesized with some tunability (10, 11). Low-generation dendrons (∼5 nm) with variable shapes and chemistries have been synthesized, and modification of their composition was shown to provide unique control on their molecular assemblies (10, 12). High-generation dendrimers of variable size (up to 30 nm) and chemistry but fixed shape (spherical) have been intensely investigated over the years in drug delivery, gene transfection, and imaging (13). Recently, cylindrical-shaped macromolecules with variable size (up to 1,000 nm) and chemistry have been accessed through the synthesis of high graft density branched polymers, called bottlebrush polymers (14, 15). The steric encumbrance of the densely packed brushes forces the polymer to adopt a semirigid 3D cylindrical conformation (15–17). Sequenced graft-through polymerization of macromonomers with different lengths has been implemented to reach a limited number of blocky shapes (18–21). The potential of these materials is highlighted by the wide range of available chemistries that have been applied to the synthesis and functionalization of bottlebrush polymers, which have translated into remarkable attributes for drug delivery, biomimicry, photonic materials, and soft elastomers (15, 16, 22, 23).

Here we present a methodology for the synthesis of bottlebrush polymers with programmable shape, size, and chemistry. Bottlebrush polymers with conical, ellipsoidal, and concave architectures (Fig. 1, Right) are synthesized with a size up to 300 nm using ring-opening polymerization (ROP) in tandem with ring-opening metathesis polymerization (ROMP) on gram scale. The essence of shape stems from varying the brush length along the polymer backbone, which is achieved by varying the rate of addition of the growing macromonomer solution into a graft-through polymerization (semibatch setup, Fig. 1, Left). Beyond the control of shape and size, this approach is compatible with a variety of chemistries; as exemplified by the synthesis of a compositionally asymmetric cone containing both asymmetric shape and chemical contrast within a single macromolecule.

Fig. 1.

(Left) Schematic of the programable semibatch reactor system. (Right) Shaped bottlebrush polymers.

Results and Discussion

We envisioned that the shape and size of bottlebrush polymers could be programmed by implementing a computer-controlled semibatch reactor setup in conjunction with a graft-through polymerization (Fig. 1, Left). With this approach, the flowrate profile of the solution of growing macromonomer would directly translate into the shape of the bottlebrush polymer, i.e., each flowrate profile will result in a unique polymer shape. The reactor setup consists of a syringe/syringe pump as the first reaction vessel, and a flask as the second vessel. In the first vessel, the macromonomers are synthesized via a controlled polymerization, while the solution is continuously fed into the second reaction vessel. The brush growth is immediately quenched upon addition to the second vessel, and the macromonomers are rapidly and quantitatively incorporated into the growing bottlebrush polymer via a graft-through polymerization. Over time, the length of the macromonomer increases in the first vessel, and the process results in a shaped bottlebrush polymer in the second vessel.

To implement the proposed shape-controlled synthesis, a few polymerizations selection criteria are considered. First, the two polymerizations should be fully compatible and orthogonal. Second, the macromonomer synthesis should be quenched readily in the second vessel. Third, the graft-through polymerization should have a very high rate of polymerization to prevent the accumulation and scrambling of macromonomers of different lengths. Grubbs third-generation (G3) catalyzed ROMP of norbornene-type monomers was selected for the graft-through polymerization (the backbone-forming reaction), as it results in very narrow polymer molecular weight dispersities at very high monomer conversion (24, 25). The ROP of lactide catalyzed by a 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was selected for the brush synthesis as an orthogonal and quenchable polymerization (26).

The polymerization rates for both brush and backbone reactions were determined to ensure the control over the bottlebrush’s shape and size was maintained. The rate constant of ROP of lactide (k_p = 200 M⁻²⋅min⁻¹; SI Appendix, section 3) was determined and extremely narrow polymer dispersities were achieved (M_w/M_n = Ɖ < 1.1) (26). The narrow polymer dispersities are a key element for maintaining shape control, as a broad polymer distribution would reduce the shape resolution. The rates of polymerization of G3-initiated ROMP of macromonomers (nor-PLA) were measured over a broad range of molecular weights (SI Appendix, section 5). In all cases, the rates of polymerization were very fast (k_obs > 1.5 min⁻¹) compared with ROP (∼10²× faster). This large difference in polymerization rates is important to ensure that the macromonomer growth and thus the feed rate of macromonomers is slow enough so that the fast ROMP is able to maintain a high macromonomer conversion; i.e., prevent the accumulation and scrambling of brushes of various lengths in the ROMP pot.

To ensure the orthogonality of ROMP and ROP a study was conducted to explore the compatibility of both polymerizations in detail. A model system using nor2 [(bicyclo[2.2.1]hept-5-en-2-yl)methyl benzoate] as a monomer for ROMP was implemented to probe the effect of ROP reagents on ROMP (SI Appendix, section 4). Only DBU was identified to be an inhibitor. Therefore, DBU must be quantitatively scavenged out of solution upon addition to the second vessel (27). Boric acid was found to be very efficient in this role as it fully quenched ROP without affecting the ROMP (with respect to rate and polymer dispersity) prior to and post-DBU quenching. Finally, we demonstrated that ROMP remained controlled under semibatch conditions by slowly feeding a solution of 500 eq of nor2 to a solution of G3 over the course of 1 h. Full monomer conversion was achieved, and the isolated polymer had the same molecular weight, as in the batch experiment (M_n = 113 kg/mol, Ɖ = 1.03).

A key feature of the methodology is that the molecular shape is a direct result of the flowrate profile [${\vartheta }_{\text{o}}$(flow rate) vs. t(time)] of liquid from vessel 1 to vessel 2. We chose to target three specific geometric shapes (cone, ellipsoid, and concave elliptical cone) to establish the methodology. However, the method can in principle be used to synthesize any axisymmetric monotonic geometry. The flowrate equations/profiles were derived using a constraint that describes the relationship between brush length with respect to backbone position (i.e., shape). A unique feature of this is that each shape and size has a different characteristic flowrate profile. The constraint for a cone, for example, is a constant, “A” (Eq. 1), which embodies the cone angle. The flowrate equation for the cone is presented in Eq. 2. A detailed derivation of the flowrate equations for all of the targeted geometries can be found in SI Appendix, section 9.

$$\text{Constant}\equiv \text{A}=\frac{{\text{N}}_{\text{brush}}}{{\text{N}}_{\text{bb}}},$$ [1]

$${\vartheta }_{\text{o}}=\left(\frac{{\text{N}}_{\text{brush}}^{\text{syn},\text{max}}}{{\text{N}}_{\text{bb}}^{\text{syn},\text{max}}}\right)\left(\frac{{\text{V}}_1}{\text{A}}\right)\left({\text{K}}_{\text{ROP}}\right){\text{e}}^{-{\text{K}}_{\text{ROP}}\text{t}}.$$ [2]

The flowrate equation is the only mathematical framework needed to synthesize shaped bottlebrush polymers. Additionally, it is possible to predict the polymerization outcomes (i.e., conversion of lactide and norbornene in both reaction vessels and M_n of brushes and bottlebrush polymers) at any time point by combining the flowrate equation with the rate laws, and the design equations for semibatch reactors (SI Appendix, section 9) (26, 28). The use of a mathematical framework to predict the polymerization outcomes provides a first-principle methodology for proving precise shape and size control. Each shape and size has its own flowrate equation and its own characteristic prediction profiles. A match between the experimental data and the predictions would validate a successful synthesis of a shaped bottlebrush, as no other macromolecule could have been synthesized. To that end, a MATLAB code was written to numerically solve the design equations (SI Appendix, section 10) and generate the predictions.

To compare an experiment directly with our predictions, we performed the synthesis of a conical-shaped polymer (${\text{N}}_{\text{brush}}^{\text{max}}=50$, ${\text{N}}_{\text{bb}}=185$) multiple times, quenching the polymerizations at different reaction time points by simultaneously halting the flow of macromonomer and injecting vinyl ether to stop ROMP. The crude polymer mixtures were analyzed by gel permeation chromatography (GPC) and NMR spectroscopy to determine the system outcomes (Fig. 2 and SI Appendix, section 6). First, the conversion of lactide and lactide buildup proceeded as predicted, which confirms that the macromonomers fed out of the syringe had the desired conical profile. Second, no residual macromonomer was detected in the graft-through polymerization vessel at any time point (macromolecule conversion >98%, SI Appendix, section 11 for detection limit) providing proof of rapid incorporation of the macromonomers into the growing bottlebrush, thus ensuring that no scrambling of brushes of different lengths occurs. Third, the experimental and the predicted bottlebrush molecular weights were in close agreement, and all bottlebrush polymers had narrow molecular weight distributions (Ɖ < 1.1). Altogether the strong agreement between prediction and experiment validates the shape and size control of the process.

Fig. 2.

Process flow diagram with predicted (line) and experimental (dots) data for the synthesis of conical bottlebrush.

The precision and flexibility of the methodology was further illustrated by synthesizing a series of conical-shaped bottlebrush polymers with different sizes, backbone lengths, and cone angles (Table 1 and SI Appendix, section 6). In all cases, the predicted parameters (molecular weights and conversions) matched the experimental values well, no residual macromonomers are detected, and the polymers remained narrowly dispersed (Ɖ ≤ 1.12). Next, the methodology was expanded to ellipsoid and concave elliptical cone shapes (Table 1). This was achieved by simply implementing the corresponding flowrate equations. Once again, NMR and GPC were used to analyze the products of the reactions. Narrow molecular weight distributions and strong agreement with predictions establish the exquisite control over shape and size. To further validate the methodology, atomic force microscopy (AFM) images of a conical-shaped polymer were collected. The size and shape observed are consistent with theoretical calculations of size (Fig. 3 and SI Appendix, section 13).

Table 1.

Predicted and experimental data for the synthesis of shape-controlled bottlebrush polymers

Entry	Shape	Composition	Prediction					Experimental data
			Nbb	Mn,brush,max	Lac buildup, %	Mn,BB	Mn,brush,max*	Lac buildup†, %	Mn,BB‡	Ɖ‡	Nor conv. (NMR)†, %
1	Conical	PLA	100	3.63	81.7	200	3.59	81.3	178	1.07	>98
2		PLA	200	3.63	81.7	400	3.55	80.7	515	1.12	>98
3		PLA	500	3.63	81.7	998	3.59	81.7	895	1.09	>98
4	Ellipsoid	PLA	200	2.48	81.7	400	2.44	81.5	522	1.13	>98
5	Concave elliptical cone	PLA	200	6.27	81.7	400	6.34	81.2	521	1.14	>98
6	Conical	PDMS	200	6.73	—	767	6.72	—	153*	1.18*	>98

M_n are in kg/mol and reaction conditions can be found in SI Appendix.

^*Data collected from GPC with respect to PLA standards for PLA and PS standards for PDMS.

^†Calculated from ¹H NMR.

^‡Data collected from triple-detect GPC.

Fig. 3.

AFM height maps for PLA cone bottlebrush on silicon surface. The blue line in the plot is the theoretical shape profile for the imaged bottlebrush.

The generality of the synthetic strategy was further showcased by expanding the chemical versatility of the process. The anionic ROP of cyclic siloxanes for the synthesis of PDMS brushes was used in place of the ROP of lactide (29). A detailed kinetic analysis and chemical compatibility study was performed, which identified trimethylsilyl chloride (TMSCl) as an effective quenching agent (SI Appendix, section 7). Polydimethylsiloxane (PDMS) conical bottlebrushes were successfully synthesized with narrow molecular weight distributions (Ɖ ≤ 1.2) and no detectable unreacted macromonomer was observed (Table 1 and SI Appendix, section 7).

Finally, as a second example illustrating the chemical versatility of the process, a compositional asymmetric cone was synthesized (30–32). This was achieved by cofeeding two macromonomers synthesis reaction mixtures, one for PLA and one for PDMS, into a single vessel of G3, boric acid, and TMSCl (Fig. 4 and SI Appendix, section 8). Analysis of the crude reaction mixture confirmed that the experimental conversions matched the predicted values, while maintaining a narrow polymer dispersity (Ɖ = 1.19). The precision of the synthesis of this complex molecular object exemplifies the chemical flexibility and shape control of the methodology. Moreover, this one-step synthesis was completed in less than 2 h, using exclusively commercially available reagents.

Fig. 4.

Synthesis of a compositional asymmetrical cone composed of PLA and PDMS arms.

Conclusion

This work establishes a scalable strategy to synthesize macromolecules with programmable shape, size, and composition. Reactor engineering principles and controlled polymerizations are leveraged to achieve the continuous control of brush length along the polymer backbone. This allowed for the programming of shape and size simply by changing the flowrate, as any particular flowrate profile will yield a bottlebrush polymer with a unique architecture. Macromolecules with conical, ellipsoidal, and concave architectures were synthesized and a mathematical model was used to confirm that precise synthetic control was achieved. The chemical versatility of the method was illustrated by the synthesis of a compositional asymmetric cone containing both asymmetric shape and compositional contrast within a single macromolecule. Overall this methodology provides an ability to independently probe the impact of macromolecules shape, size, and chemistry for the development of new materials.

Methods and Materials

Details of all procedures can be found in SI Appendix.

The general procedure for the synthesis of shaped bottlebrushes is as follows: To a glass vial, lactide and nor1 are dissolved in THF. The polymerization was initiated by adding DBU dissolved in THF. This reaction mixture was immediately sucked up into a syringe and the needle was pushed through a septum of a round-bottom flask containing B(OH)₃ and G3 in THF. This setup (syringe and round-bottom flask) was set in a syringe pump. The reaction mixture was added according to a specified flow profile. At the end of the reaction a large excess of ethyl vinyl ether (large excess with respect to [Ru]) was immediately added to the reaction mixture. The reaction mixture was poured into methanol and a centrifuge was used to isolate the resulting polymer.