Rapid flow-based synthesis of poly(3-hexylthiophene) using 2-methyltetrahydrofuran as a bio-derived reaction solvent

We report the synthesis of poly(3-hexylthiophene) (P3HT) by Grignard metathesis (GRIM) polymerization using the bio-derived ‘green’ solvent 2-methyltetrahydrofuran (2-MeTHF). Using a standard flask-based reaction, the molecular weight distribution, regioregularity and product yield were found to be similar to those obtained under equivalent conditions using tetrahydrofuran (THF) as a reaction solvent. The synthesis was subsequently adapted to a novel “tube-in-shell” droplet-based flow reactor, using a newly developed high-solubility catalyst derived from nickel(II) bromide ethylene glycol dimethyl ether complex (Ni(dme)Br2) and 1,3-bis(diphenylphosphino)propane (dppp). Use of the new catalyst together with an increased reaction temperature of 65 oC (enabled by the higher boiling point of 2-MeTHF) resulted in an approximate four-fold increase in reaction rate compared to a standard THFbased synthesis at 55 oC, with full conversion reached within one minute. The purified flowsynthesized polymer had an Mw of 46 kg mol, a low PDI of 1.4, and a regioregularity of 93 %, indicating the suitability of flow-based GRIM polymerization in 2-MeTHF for the highthroughput synthesis of high quality P3HT.

yield, and the ease with which molecular weight may be tuned through simple changes to the reaction conditions. [3,4] Scheme 1 shows a two-step, one-pot GRIM polymerization route for the preparation of P3HT. In its usual form, 2,5-dibromo-3-hexylthiophene (1) is first activated with one equivalence of a Grignard reagent in an ether-based solvent, typically tetrahydrofuran (THF), yielding a mixture of two thienyl-Grignard regioisomers (2a and 2b). After completion of the initial metathesis, a nickel-diphosphine catalyst, typically [1,3-bis(diphosphinopropane)]nickel(II) chloride (Ni(dppp)Cl 2 ), is added to initiate Kumada-Yamamoto cross-couplingknown more widely as Kumada catalyst transfer polymerization (KCTP) -to form the conjugated polymer (3). The polymerization is quenched using a protic (often acidified) non-solvent that also induces precipitation of the polymer, enabling isolation over a filter.
When isopropylmagnesium chloride (iPrMgCl) is used as the Grignard reagent, the ratio of 2a to 2b is approximately four to one, [5] with the minority isomer 2b being sterically inactive towards Ni(dppp)Cl 2 and the majority isomer 2a undergoing quasi-living chain-growth to form regioregular P3HT, [2,6] suitable for organic electronics applications. [7,8] The standard GRIM polymerization synthesis route as described above is effective for the lab-scale synthesis of regioregular P3HT. However, the use of THF as a process solvent presents significant difficulties for larger-scale manufacturing owing to the energy intensive, non-renewable nature of its production. [9] Here we investigate the use of the bioderived solvent 2-methyltetrahydrofuran (2-MeTHF) as a greener alternative to THF. We show that 2-MeTHF can be used as a direct replacement for THF in the flask-based synthesis of P3HT, yielding polymer with similar material properties under equivalent reaction conditions. We further show that the reaction procedure in 2-MeTHF may be adapted to flow synthesis in a droplet-based microreactor, where the higher boiling point of 2-MeTHF (~80 °C [10]) allows the reaction to be carried out at temperatures of up to 65 °C, leading to substantially faster reaction rates. In combination with a new catalyst derived from nickel(II) bromide ethylene glycol dimethyl ether complex (Ni(dme)Br 2 ) and 1,3-bis(diphenylphosphino)propane (dppp), we find that it is possible to achieve full conversion in under one minute, while still achieving regioregularities comparable to those obtained using Ni(dppp)Cl 2 . The described modifications to the standard GRIM polymerization route are of direct relevance to the large-scale manufacturing of P3HT, allowing for increased materials throughput whilst at the same time reducing environmental impact.

Results and Discussion
THF is the most widely used solvent for GRIM polymerization, with only a few isolated examples of alternative solvents such as o-dichlorobenzene being used in its place.
[11] While THF is an excellent Lewis base for Grignard (and other organometallic) chemistries, its production is highly energy intensive. [9] In recent years there has been a trend towards the use of bio-derived, green solvents as replacements for hazardous and/or environmentally-damaging solvents. [12] 2-methyltetrahydrofuran (2-MeTHF) is one such solvent that has been developed as a greener alternative to THF. [13] Derived from inedible biomass, 2-MeTHF is a close derivative of THF and is accordingly well-suited to Grignard chemistry. Further advantages of 2-MeTHF include: (i) a higher boiling point (78-80 °C) compared to THF (66-67 °C); (ii) low miscibility with water; (iii) favorable azeotropes with water and alcohols, enabling easier production of anhydrous solvent; and (iv) a favorable preliminary safety assessment. [14,15] 2-MeTHF has been successfully used as a solvent for a range of small molecule chemistries, including organometallic chemistries. [12,14,16] Here we evaluate its suitability for the synthesis of P3HT by Grignard metathesis polymerization, with a view to reducing the environmental impact of P3HT synthesis and exploiting its higher boiling point to achieve higher reaction rates.
To assess the suitability of 2-MeTHF for use as a solvent for P3HT synthesis, we adapted a flask-based synthesis procedure using THF that we had previously optimized for the production of high molecular weight P3HT with weight-average molecular weight (Mw) greater than 100 kg mol -1 . [17] (We have recently shown that P3HT prepared using this procedure can yield high performance P3HT:fullerene organic photovoltaic devices with power conversion efficiencies of up to 7 %, using indene-C 60 bis-adduct as the fullerene acceptor [18]). Two samples B1 and B2 were prepared under equivalent conditions (see Experimental Methods), using THF and 2-MeTHF respectively. The syntheses were carried out at 55 °C -the highest reaction temperature that can be used with THF without it simmering or boiling in the flask (and thereby causing unwanted quenching of the polymerization on the walls of the flask during the course of the reaction).
After purification, sample B1 was recovered with a yield of 86 % (assuming a four to one ratio of 2a : 2b, with only 2a being active towards the catalyst). Using refractive-index size-exclusion chromatography (RI-SEC), B1 was found to have a Mw of 134 kg mol -1 and a PDI of 1.62, see Table 1 and Figure SI1a. By analyzing the α-methylene region of the 1 H NMR spectrum [19], the regioregularity was determined to be 99 % (see Fig. SI1b) in accordance with the regio-selective nature of the chosen GRIM-based synthesis. [17] B2 was recovered with a high yield of 94 % after purification (assuming the same four to one ratio of active 2a to inactive 2b). There was only a small difference in the molecular weight distribution compared to B1 (see Figure SI1a), with the Mw and PDI being broadly similar at 137 kg mol -1 and 1.66, respectively. The RR was also similar at 99 %.
The higher boiling point of 2-MeTHF (80 ºC) allows the reaction to be carried at higher temperatures of up to 75 °C without simmering or boiling in the flask. A third sample B3 was prepared in 2-MeTHF at 75 °C and recovered at 85 % yield after purification. The Mw and PDI were slightly lower than for B1 and B2 at 118.0 kg mol -1 and 1.53, respectively. The regioregularity was also slightly lower at 98%, consistent with the lower molecular weight.
On the basis of the results above, it is evident that under otherwise identical conditions 2-MeTHF can serve as a direct substitute for THF without substantially affecting the properties or yield of the final product. Moreover, its higher boiling point allows the reaction to be carried out at higher temperatures of up to 75 °C, leading to faster reaction rates and shorter conversion times (see below).

Flow Synthesis
Having confirmed the suitability of 2-MeTHF for the flask-based synthesis of P3HT, we investigated its suitability for use in (droplet-based) flow reactors. Flow synthesis is of significant interest for the synthesis of advanced materials such as conjugated polymers due to its amenability to high volume manufacturing, allowing production rates of a few tens [20] to several hundreds [21,22] of grams per day to be readily achieved in even small lab-scale reactors. [11,[20][21][22][23][24][25][26] The majority of reports of polymer synthesis in flow have used commercial singlephase flow reactors, in which the reagents are mixed together and pumped through the reactor in a continuous stream of a single solvent. Such reactors, however, are susceptible to fouling as a result of polymer deposition on the reactor walls. This is a particular issue for industrial manufacturing, where fouling is a major cause of product drift and reactor downtime. We have previously reported the use of droplet-based flow reactors as a means of preventing reactor fouling during the flow synthesis of conjugated polymers. [20,24] In this approach monomer feedstock is injected into a fast-flowing stream of immiscible carrier fluid, forming a stream of near-identical microliter-sized monomer droplets that act as discrete selfcontained microliter reaction vessels. The small droplet size ensures rapid equilibration of composition and temperature, and so provides a highly uniform environment for polymerization. Importantly, since materials throughput can be raised independently of droplet volume (by ramping up the rate of droplet generation, while keeping the droplet size fixed), production levels can in principle be scaled-up indefinitely without detriment to product quality.
The carrier fluid is chosen to wet preferentially to the channel walls, ensuring the droplets are kept beneficially isolated from the channel walls and so cannot cause fouling of the reactor. For the work described here perfluorinated polyether (PFPE) was used as the carrier fluid in combination with polytetrafluoroethylene (PTFE) reactor tubing. PFPE wets the PTFE tubing preferentially over most organic solvents, resulting in stable droplet flow over a wide range of temperatures. [27][28][29] It is not consumed during the flow process and so may be reused, either by recovering it manually from the product at the outlet or by continuously recycling it in-line. [28,30,31] In the flask-based synthesis of P3HT described above, the catalyst was added in solid form to the thienyl-Grignard. In flow-based syntheses, however, it is preferable to dissolve the nickel catalyst to achieve good control over the molecular weight. At full conversion, the molecular weight average is primarily determined by the initial molar ratio of monomer to catalyst, with each catalyst molecule propagating the growth of an individual chain. Hence, a low monomer to catalyst ratio will lead to a small number of long chains, while a high monomer to catalyst ratio will lead to a large number of short chains. This mechanistic property may be exploited to tune the molecular weight of P3HT in both flaskand flow-based reactions. [3,4,11,20] While high weight P3HT (as prepared above) is often preferred for small-scale processing from chlorinated solvents, lower molecular weight material (< 50 kg mol -1 ) is typically preferred for processing from non-chlorinated solvents since it dissolves more readily. Such low weight materials can be difficult to access in flow using the standard Importantly, Ni(dppp)Br 2 retains the catalytic Ni(0)(dppp) functionality required for KCTP [3,4], with the bromide anions merely acting to improve the solubility of the initial Ni(II) precursor.
We have found that the catalyst remains soluble at concentrations up to 26 mM (supported by a proportionate increase of dppp) in THF compared to ~2 mM for Ni(dppp)Cl 2 . Although stable in solution under an inert atmosphere, the catalyst rapidly degrades if exposed to air.
For the work reported here the catalyst was therefore generated in-situ in an argon atmosphere (see Experimental Methods).
To demonstrate the feasibility of applying Ni(dppp)Br 2 to the flow synthesis of low molecular weight P3HT in 2-MeTHF, a flow synthesis was carried out using 3.1 mM Ni(dppp)Br 2 -approximately twice the concentration that can be achieved using standard Ni(dppp)Cl 2 . Figure 1 shows a schematic of the experimental set up. Separate solutions of 3 As we have previously reported for Ni(dppp)Cl2 [23], Ni(dppp)Br2 requires an excess of 1,3bis(diphenylphosphino)propane (dppp) to inhibit catalyst deactivation via ligand dissociation. Addition of excess dppp to Ni(dme)Br2 in solution results in an immediate color change from pink to brownindicative of the Ni(dppp)Br2 species forming. 4 In early stage tests we found a strong correlation between the [dppp]:[Ni] ratio and the molecular weight distribution of the polymer up to 2.1 equivalences. Above 2.1 equivalences the molecular weight distribution was found to be insensitive towards the ratio of [dppp]: [Ni]. A value of 2.5 equivalences is chosen in order to be safely above the threshold. thienyl-Grignard (0.25 M) and Ni(dppp)Br 2 (3.1 mM) were prepared in anhydrous 2-MeTHF as described under Experimental Methods. After cooling to room temperature, the solutions were transferred into separate oven-dried 10 mL gas-tight syringes (Hamilton) and sealed prior to use. A third 50 mL gas-tight syringe (SGE) was filled with argon-sparged PFPE (Galden HT-170, Solvay Solexis) and sealed prior to use. The three fluids were connected to a threeinlet/one-outlet PTFE droplet generator, fabricated using a four-axis milling machine to a previously reported design (Fig. 1a). [32] In use, the droplet generator produces a stable stream of near-identical droplets, as shown in the inset photograph of Figure  The flow synthesis was carried out using a novel "tube-in-shell" reactor that allowed the droplet stream to be heated without recourse to a cumbersome oil-bath (Fig. 1b). The reactor was formed from two coaxial tubes of approximate length 1 m: the droplet stream from the droplet generator was injected into the central tube (ID 1 mm, ~785.4 µL), while an outer jacket of temperature-controlled water was constantly recirculated through the void between the outer wall of the central tube and the inner wall of the outer tube (ID 3 mm). The water jacket was maintained at a constant temperature of approximately 65 °C using a small recirculating water heater that kept the water in rapid circulation via a pair of junctions at each end of the reactor (see schematic in Fig. 1c). With a pump speed of several hundred milliliters per minute, the temperature difference between the inlet and the outlet was much less than 1 °C, ensuring virtually constant heating along the full length of the reactor. On exiting the central capillary, the droplet stream was passed into a methanol-filled collection vessel to quench the reaction (Fig. 1d). Complete details of the reactor design can be found in SI Section E.
In initial testing it was determined that using 2-MeTHF as the reaction solvent allowed  Figure 2 shows the molecular weight distributions for the four crude samples, which were virtually identical to each other. The weight-average molecular weights were all approximately 44 kg mol -1 (see Table 2  The ability to produce high quality polymers despite a four-fold increase in throughput is highly beneficial from a manufacturing perspective, significantly lowering production costs. When combined with the previously noted environmental advantages, these early results provide a strong case for the use of 2-MeTHF (and related bio-derived solvents) for GRIM-type polymerization chemistry.

Conclusion
In was carried out using the same procedure as for the flask-synthesized polymers.