Recent years have witnessed increased interest in systems that are capable of supporting multistep chemical processes without the need for manual handling of intermediates. These systems have been based either on collections of batch reactors1 or on flow-chemistry designs2,3,4, both of which require considerable engineering effort to set up and control. Here we develop an out-of-equilibrium system in which different reaction zones self-organize into a geometry that can dictate the progress of an entire process sequence. Multiple (routinely around 10, and in some cases more than 20) immiscible or pairwise-immiscible liquids of different densities are placed into a rotating container, in which they experience a centrifugal force that dominates over surface tension. As a result, the liquids organize into concentric layers, with thicknesses as low as 150 micrometres and theoretically reaching tens of micrometres. The layers are robust, yet can be internally mixed by accelerating or decelerating the rotation, and each layer can be individually addressed, enabling the addition, sampling or even withdrawal of entire layers during rotation. These features are combined in proof-of-concept experiments that demonstrate, for example, multistep syntheses of small molecules of medicinal interest, simultaneous acid–base extractions, and selective separations from complex mixtures mediated by chemical shuttles. We propose that ‘wall-less’ concentric liquid reactors could become a useful addition to the toolbox of process chemistry at small to medium scales and, in a broader context, illustrate the advantages of transplanting material and/or chemical systems from traditional, static settings into a rotating frame of reference.
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All data that support the findings of this study are available within the Article and its Supplementary Information, or from the corresponding author upon reasonable request.
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This research was supported by the Institute for Basic Science, Korea (project code IBS-R020-D1). B.M.-K. and T.K. were also supported by the National Science Center, NCN, Poland under the Symfonia Award (number 2014/12/W/ST5/00592). M.D. acknowledges partial support from the National Science Center, NCN, Poland under the Maestro Award (number 2018/30/A/ST5/00529).
A patent covering the layered liquid reactors described in this work (number WO2020/153739) has been filed by the Institute of Basic Science, Republic of Korea, listing O.C., M.D., B.M.-K., Y.I.S. and B.A.G. as inventors.
Peer review information Nature thanks Panagiota Angeli, Jon Clardy and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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This file contains Supplementary Information Sections 1-8, including Supplementary Text and Data, Supplementary Figures 1-31, Supplementary Table 1 and Supplementary References – see contents page for details.
Video 1 Sequential loading of liquids by deposition on the floor of the rotating chamber. Video (at 10× acceleration) of injecting seven pairwise immiscible liquids (specified in the description of Supplementary Fig. 1) into an initially empty rotor. Liquids are dispensed from syringes pointing towards the floor of the rotating chamber. Owing to the combination of centripetal and Coriolis forces, droplets or jets of these liquids are spread over a large area of the bottom surface of the chamber before contacting the liquid layers already formed—this spreading prevents thin layers from being penetrated/disrupted by impact of larger droplets, but also poses a risk of depositing liquid or solid residues on the floor (and ceiling) of the chamber, especially when volatile solvents evaporate from droplets. This technique of building a multilayer liquid assembly is suitable for very thin layers, but suboptimal in terms of avoiding cross-contamination (between liquids that are not intended for direct contact) or keeping strictly prescribed amounts of liquid from escaping the chamber by evaporation.
Video 2 Demonstration of different ways of delivering or drawing liquids to and from a rotating chamber. Four different techniques are shown: (i) The same as in Video 1, but real-time: shown is the process of adding one layer to three existing layers. (ii) Supplying the liquids through a system of branching channels, shown in Fig. 1c and discussed in the main text. The newly introduced liquid moves rapidly through the unoccupied part of the main, straight channel (flowing mostly along one of the side walls of this channel) and, when in the occupied part, turns to the first branch whose outlet is submerged (i.e., already covered by previous liquids in the chamber). This method is cleaner than (i), but less general, as the minimum thickness of the layer is limited by the distance between outlets of branching channels. (iii) Injecting the liquid to one of the already existing layers via a single channel embedded in the floor of the chamber. The liquid is pipetted into the O-ring-sealed port at the axis of the rotor. (iv) Using the same port to withdraw liquids from the chamber.
Video 3 Mixing the liquids within layers, without disrupting the layers. When the chamber rotates with constant velocity, the multilayer assembly of liquids rotates as a rigid body, limiting any mixing within layers to slow diffusion. However, rapid changes in the rotational speed of the rotor (shown is a rapid decrease of the speed from 3,600 rpm to about 3,000 rpm and increase back to 3,600 rpm), combined with the inertia of the rotating liquids, creates eddies that mix the content of layers, yet keep the integrity of the stack (unless the acceleration of the rotor is too high).
Video 4 Demonstration of a very thin liquid layer forming between two immiscible phases of both larger and smaller densities. Real-time video of three mutually immiscible liquids (FC-40, hexadecane and orange dyed water; see Fig. 3c, d) in the rotor (the same as in Fig. 2a–d) accelerating from 0 to 3,600 rpm within about 2 seconds. Initially, all three phases (including the tiny amount of water) disperse owing to high shear forces, yet almost as soon as the rotor stops accelerating, the liquids form a three-layer system, with thickness of the water layer ~150 μm.
Video 5 Injecting a new, immiscible layer into the middle of an existing, continuous (single-phase) density gradient. Initially, the rotor contains two mutually miscible liquids: dibromomethane (density 2.48 g/ml) and tetralin (1,2,3,4-tetrahydronaphtalene, 0.973 g/ml); their mutual boundary is already blurred due to diffusion and convective mixing caused by flows of liquid during filling of the chamber (by pipetting them sequentially on the floor of the rotor rotating at 1,080 rpm). The new, immiscible liquid is delivered through the hole in the floor, located at the presumed mid-point of the original density gradient, i.e., at the zone of density ~1.73 g/ml, matching the density of the newly injected liquid (water solution of CsCl dyed with Alizarin Red S). This new liquid is initially fragmented, but as its volume increases, it assembles into a full ring separating the lighter and heavier parts of the original organic phase.
Video 6 Injecting a new, miscible liquid into the middle of an existing continuous density gradient. The system is as in Supplementary Video 5 but the injected fluid of density ~1.73 is miscible with both the original organic liquids forming the initial density gradient (in fact, this newly pumped liquid is 50/50 v/v mixture of these liquids dyed with Oil Red EGN). The ring of the injected liquid is thinner than in the case of Supplementary Video 5 but because of diffusion, it slowly fades out, as seen at the end of the video (forwarded by 20 minutes).
Video 7 Converting one-phase system into five-layer two-phase system and further operations (addition and mixing) on one of its layers. The video complements experiments described in Supplementary Information section 2 and Supplementary Figs. 3, 4. It is divided into 11 short sections preceded by intertitles and corresponding one-to-one to panels of Supplementary Figs. 3a–f, 4a–e.
Video 8 Collage of three videos (5 times accelerated) showing continuous, reversible transition from stack to concentric layers and back to stack. The experimental system as in Supplementary Fig. 13a, with different ways of illumination: narrow back light (on the left), wide back light (centre) and stroboscopic light (on the right) synchronized to the camera framerate, 25 frames per second. In real time, rotation speed varies from 0 to 5,576 rpm within 150 seconds and then comes back to 0 within another 150 seconds.
Video 9 Toxicity test of density-modified broths and oils considered for the use with bacteria in rotating layers. Detailed information is provided in Supplementary Information section 6.3. Labels enumerating vials in the video are also given above graphs in Supplementary Fig.29; red colour for larger and blue for smaller initial concentration of bacteria.
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Cybulski, O., Dygas, M., Mikulak-Klucznik, B. et al. Concentric liquid reactors for chemical synthesis and separation. Nature 586, 57–63 (2020). https://doi.org/10.1038/s41586-020-2768-9
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