In the last decade flow reactors for material synthesis were firmly established, demonstrating advantageous operating conditions, reproducible and scalable production via continuous operation, as well as high-throughput screening of synthetic conditions. Reactor fouling, however, often restricts flow chemistry and the common fouling prevention via segmented flow comes at the cost of inflexibility. Often, the difficulty of feeding reagents into liquid segments (droplets or slugs) constrains flow syntheses using segmented flow to simple synthetic protocols with a single reagent addition step prior or during segmentation. Hence, the translation of fouling prone syntheses requiring multiple reagent addition steps into flow remains challenging. This work presents a modular flow reactor platform overcoming this bottleneck by fully exploiting the potential of three-phase (gas–liquid–liquid) segmented flow to supply reagents after segmentation, hence facilitating fouling free multi-step flow syntheses. The reactor design and materials selection address the operation challenges inherent to gas–liquid–liquid flow and reagent addition into segments allowing for a wide range of flow rates, flow ratios, temperatures, and use of continuous phases (no perfluorinated solvents needed). This “Lego®-like” reactor platform comprises elements for three-phase segmentation and sequential reagent addition into fluid segments, as well as temperature-controlled residence time modules that offer the flexibility required to translate even complex nanomaterial synthesis protocols to flow. To demonstrate the platform's versatility, we chose a fouling prone multi-step synthesis, i.e., a water-based partial oxidation synthesis of iron oxide nanoparticles. This synthesis required I) the precipitation of ferrous hydroxides, II) the addition of an oxidation agent, III) a temperature treatment to initiate magnetite/maghemite formation, and IV) the addition of citric acid to increase the colloidal stability. The platform facilitated the synthesis of colloidally stable magnetic nanoparticles reproducibly at well-controlled synthetic conditions and prevented fouling using heptane as continuous phase. The biocompatible particles showed excellent heating abilities in alternating magnetic fields (ILP values >3 nH m² kg_Fe⁻¹), hence, their potential for magnetic hyperthermia cancer treatment. The platform allowed for long term operation, as well as screening of synthetic conditions to tune particle properties. This was demonstrated via the addition of tetraethylenepentamine, confirming its potential to control particle morphology. Such a versatile reactor platform makes it possible to translate even complex syntheses into flow, opening up new opportunities for material synthesis.

中文翻译：

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多功能无污染多步流动反应器平台：氧化铁纳米粒子部分氧化合成示范

在过去十年中，用于材料合成的流动反应器稳固地建立起来，展示了有利的操作条件、通过连续操作的可重复和可扩展的生产，以及合成条件的高通量筛选。然而，反应器结垢通常会限制流动化学和常见的结垢预防方法分段流程是以缺乏灵活性为代价的。通常，将试剂送入液体段（液滴或液滴）中的困难限制了使用分段流的流动合成到简单的合成协议，在分段之前或期间只需要一个试剂添加步骤。因此，将需要多个试剂添加步骤的易结垢合成转化为流动仍然具有挑战性。这项工作提出了一个模块化的流动反应器平台，通过充分利用三相（气-液-液）分段流的潜力在分段后供应试剂来克服这一瓶颈，从而促进无污染的多步流合成。反应器设计和材料选择解决了气-液-液流动和试剂添加到片段中所固有的操作挑战，允许各种流速、流量比、温度和连续相的使用（不需要全氟化溶剂）。这种“Lego®-like”反应器平台包括用于三相分割和顺序将试剂添加到流体段的元件，以及温度控制的停留时间模块，这些模块提供了将复杂的纳米材料合成协议转化为流动所需的灵活性。为了展示平台的多功能性，我们选择了容易结垢的多步合成，即，氧化铁纳米粒子的水基部分氧化合成。该合成需要 I) 氢氧化亚铁沉淀，II) 添加氧化剂，III) 温度处理以启动磁铁矿/磁赤铁矿形成，以及 IV) 添加柠檬酸以增加胶体稳定性。该平台促进了在良好控制的合成条件下可重复地合成胶体稳定的磁性纳米粒子，并使用庚烷作为连续相防止结垢。生物相容性颗粒在交变磁场中表现出出色的加热能力（ILP 值 >3 nH m ² kg _Fe ^-1)，因此，它们具有磁热疗癌症治疗的潜力。该平台允许长期运行，以及筛选合成条件以调整粒子特性。通过添加四亚乙基五胺证明了这一点，证实了其控制颗粒形态的潜力。这种多功能的反应器平台使得将复杂的合成转化为流动成为可能，为材料合成开辟了新的机会。