A new strategy to access highly monodisperse, heterobifunctional linear polyethylenglycols (PEGs) has been designed. This was built around unidirectional, iterative chain extension of a 3-arm PEG homostar. A mono-(4,4'-dimethoxytriphenylmethyl) octagol building block, DmtrO-EG8-OH, was constructed from tetragol. After six rounds of chain extension, the monodisperse homostar reached the unprecedented length of 56 monomers per arm (PEG2500). The unique architecture of the synthetic platform greatly assisted in facilitating and monitoring reaction completion, overcoming kinetic limitations, chromatographic purification of intermediates, and analytical assays. After chain terminal derivatisation, mild hydrogenolytic cleavage of the homostar hub provided heterobifunctional linear EG56 chains with a hydroxyl at one end, and either a toluene sulfonate, or a tert-butyl carboxylate ester at the other. A range of heterobifunctional, monodisperse PEGs was then prepared having useful cross-linking functionalities (-OH, -COOH, -NH2, -N3) at both ends. A rapid preparation of polydisperse PEG homostars, free of multiply cross-linked chains, is also described. The above approach should be extendable to other high value oligomers and polymers.

Reducing solvent consumption in the chemical industries is increasingly becoming a topic of interest. The field of organic solvent nanofiltration (OSN) has markedly evolved in the past decade, and effective membranes are now available that can withstand aggressive solvents while completely rejecting small solutes at the lower end of the nanofiltration range (100–2000 g·mol–1). With such membranes in hand and the advantages of membrane modularity, it is now possible to design innovative configurations to drastically reduce solvent consumption and enhance sustainability of downstream processes. Notably, a membrane-based solvent recovery configuration reported in our group has opened a new market for OSN membranes. In this work, the current state-of-the-art OSN membranes are screened, and a possible operation window for solvent recovery is identified. In tandem, to tackle the high solvent consumption challenge of membrane-based separation, we improved the solvent recovery configuration by combining both solute separation and solvent recovery in situ. The resultant system effectively performs the desired separation without any addition of extra solvent, thereby reducing solvent consumption to nearly zero. A model system comprising roxithromycin pharmaceutical and triphenylmethanol impurity is employed to illustrate that the proposed configuration allows constant volume diafiltration to be performed without any addition of fresh solvent. Parameters affecting the separation have been identified and validated experimentally or via modeling, and theoretical limitations are critically analyzed. The operability and carbon footprint have been compared with conventional solvent recovery units (e.g., distillation and adsorption). The present work reinforces that OSN is a leading separation technology in the process intensification movement of the fine chemicals sector.

Protein crystallisation has immense potential to be used for separation and formulation applications on an industrial scale. Crystallisation under static condition is often limited by the diffusion of molecules from the bulk solution to the growing crystal surface. This results in a lower overall yield of the product and longer crystallisation periods. Hence, protein crystallisation under flow conditions has attracted attention with the capability to improve the convective protein transport, reducing the crystallisation time and improving yield. In this study, we investigate the effects of flow, specifically intermittent oscillatory flow on protein (insulin) crystallisation. It was observed that the nucleation and crystal yield is very much influenced by the flow conditions and herein we present some key observations in insulin crystallisation conducted under intermittent oscillatory flow. For oscillatory flow velocities ranging from 6 to 16 mm/min at a frequency of 1 cycle/min, a considerable increase in nucleation has been observed with an increase in flow rate resulting in the formation of large number of crystals in tubes with flow compared to the stationary tubes. Also 50% yield for flow crystallisation was achieved in contrast to only 24% yield for the stationary growth over the 48 hour period. The flow condition was thus found to affect the number and size of crystals. In addition, the intermittent flow pattern utilised in this study helps to separately understand the influence of flow on nucleation and crystal growth. The flow strategy proposed herein could potentially be utilised to optimise crystallisation processes for proteins so as to be used in downstream separation and formulation of products.

Synthetic chemists have devoted tremendous effort towards the production of precision synthetic polymers with defined sequences and specific functions. However, the creation of a general technology that enables precise control over monomer sequence, with efficient isolation of the target polymers, is highly challenging. Here, we report a robust strategy for the production of sequence-defined synthetic polymers through a combination of liquid phase synthesis and selective molecular sieving. The polymer is assembled in solution with real time monitoring to ensure couplings go to completion, on a three-armed star-shaped macromolecule to maximise efficiency during the molecular sieving process. This approach is applied to the construction of sequence-defined polyethers, with sidearms at precisely defined locations that can undergo site-selective modification after polymerisation. Using this versatile strategy, we have introduced structural and functional diversity into sequence-defined polyethers, unlocking their potential for real-life applications in nanotechnology, healthcare and information storage.Natural macromolecules, such as nucleic acids and proteins, are heteropolymers with perfectly defined chain length, monomer sequence and chirality. This precise control of the primary sequence provides structural and functional diversity sufficient to generate the molecular complexity required by all living organisms 1,2 . Polymer chemists have employed strategies such as single monomer insertion 3,4 , tandem monomer addition 5 , kinetic control 6 , segregated templating 7,8 , and sequential growth polymerisation 9,10 , to provide polymers with narrowly disperse, but not uniform, chain lengths and approximately controlled sequences. Nevertheless, these sequence-controlled approaches cannot compete with the precision of nature. To prepare truly uniform sequence-defined polymers, iterative synthesis can afford the required nature-like degree of control over the final sequence. In iterative synthesis specific monomers are added one-at-a-time to the end of a growing polymer chain, reaction debris is then separated from the chain extended polymer, and the cycle is repeated using the next monomer in the sequence 11,12 . Solid-phase iterative synthesis 13 is the premiere method for preparation of sequence-defined polymers, mainly because of the simple reaction and purification processes (i.e. filtration and washing), as well as its ease of automation 14 . However, the insoluble solid supports are often expensive, and the purity of the growing polymer is not readily monitored during synthesis 7,12 . Furthermore, the rates of solid-phase coupling reactions are limited by diffusion into the solid support, ultimately leading to a decline in coupling yields and accumulation of deletion errors 15 . Moreover, solid-phase synthesis is generally difficult to scale up, precluding many industrial applications, particularly in materials science 7,10,12 .Consequently, liquid-phase iterative synthetic methods have long been proposed to ove...

Highly monodisperse, heterobifunctional poly(ethylene glycol) (PEG) was prepared by iterative chain extension of a PEGylated homostar using an octagol (EG 8 ) building block to give MeO-EG 24 -OH in high purity. The branched structure facilitated purification of intermediates by chromatography, and mono-functionalization of the chain termini. This approach should be extendable to other classes of oligomers.

For separation of a two-component mixture, a three-stage organic solvent nanofiltration (OSN) process is presented which comprises of a two-stage membrane cascade for separation with a third membrane stage added for integrated solvent recovery, i.e. solvent recycling. The two-stage cascade allows for increased separation selectivity whilst the integrated solvent recovery stage mitigates the otherwise large solvent consumption of the purification. This work explores the effect of washing the solvent recovery unit at intervals in order to attain high product purities with imperfect solvent recovery membranes possessing less than 100 % rejection of the impurity. This operation attains a purity of 98.7 % through semi-continuous operation with two washes of the solvent recovery stage, even when imperfect membranes are used in a closed-loop set-up. This contrasts favourably with the 83.0 % maximum purity achievable in a similar set-up with a single continuous run. The process achieves slightly lower (-0.7 %) yield of around 98.2 % compared to a continuously operated process without solvent recovery but consumes approx. 85 % less solvent (theoretical analysis suggests up to 96 % reduction is possible). 9 different membranes, both commercial (GMT, Novamem, SolSep) and in-house fabricated, are screened and tested on a separation challenge associated with the synthesis of macrocycles -amongst the membrane materials are polyimide (PI), polybenzimidazole (PBI) and, polyetheretherketone (PEEK).3

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In the version of this Article originally published, the authors inadvertently cited ref. 10 in two places in the first paragraph. They would like to clarify that it should not have been cited in the sentence that starts "Polymer chemists have employed strategies such as single monomer insertion... " as it mistakenly implied that the IEG+ method described in ref. 10 could not produce unimolecular polymers; it can do so, as was demonstrated in ref. 10. The authors would also like to clarify that ref. 10 should not have been cited in the sentence that starts "Moreover, solid-phase synthesis is generally difficult to scale up... ", as it implied that ref. 10 uses solid-phase synthesis; it does not, and is a purely liquid-phase process. The citation of ref. 10 has now been removed from these two sentences, but has been included elsewhere in the first two paragraphs of the Article as follows. In the first paragraph, at the end of the sentence "In iterative synthesis, specific monomers are added one at a time, or as multiples, to the end of a growing polymer chain, then reaction debris is separated from the chain extended polymer, and the cycle is repeated using the next monomer in the sequence 10-12. "; this sentence has been further amended to indicate multiple monomers can also be added. The reference has also been added to the end of the first sentence of the second paragraph, which starts "Consequently, liquid-phase iterative synthetic methods... ", and in the third sentence of that paragraph, which now starts "For example, Johnson 10 , Whiting. ... ".