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In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/chemcomm Page 1 of 11 Please doChemComm not adjust margins Journal Name ARTICLE Reactions in ultra-small droplets by tip-assisted chemistry M. Guardingo, a,b,†, * F. Busqué b and D. Ruiz-Molina a, * Received 00th January 20xx, Accepted 00th January 20xx The confinement of chemical reactions within small droplets has received much attention in the last few years. This approach has been proved successful for the in-depth study of naturally occurring chemical processes as well as for the DOI: 10.1039/x0xx00000x synthesis of different sets of nanomaterials with control over their size, shape and properties. Different approaches such www.rsc.org/ as the use of self-contained structures or microfluidic generated droplets have been followed over the years with success. However novel approaches have emerged during the last years based on the deposition of femtolitre-sized droplets on surfaces using tip-assisted lithographic methods. In this feature article we review the advances made towards the use these ultra-small droplets patterned on surfaces as confined nano-reactors. nanomaterials, droplets can act as templates to control Introduction parameters such as particle size and shape or surface texture 5 and thus, to tune morphology-size-property relationships. So Femtolitre chemistry has arisen in the last few years as an far, different approaches have been followed to generate Manuscript exciting approach to synthesize nanoscale materials in a highly miniaturized droplet-based reactors. The most extended controlled manner. In combination with lithographic and procedures make use of self-contained structures (like droplet micro/nano-fabrication techniques, it has opened the door to emulsions, liposomes, micelles and protein cages) or the creation of large and dense arrays of nano-reaction vessels microfluidic-generated droplets. An alternative methodology for high-throughput screening, combinatorial 1 consisting in depositing small droplets on surface using tip- chemistry/biology or chemical synthesis. Beyond the need for assisted lithographic methods has emerged in the last few nanostructured materials, there are several other scientific years. With this approach the droplets can be used as confined motivations to conduct chemistry at this scale. A femtolitre -15 3 reactors to precisely control the position of the resulting (fL= 10 L, 1 µm ) is approximately the volume of a bacterial materials on the substrate. The interest of this methodology cell, and the ultimate chemistry of life takes place at this ultra- -12 3 relies in the reduction of the number of steps needed to Accepted small scale that ranges from picolitres (pL=10 L, 10 µm ) to -18 3 2 pattern functional materials on a surface, as the synthesis and attolitres (aL=10 L, 100 nm ). Reproducing these highly patterning processes are performed simultaneously. crowded and confined conditions is therefore essential to In this feature article we review recent research involving understand their effect on the thermodynamics and kinetics of femtolitre-sized reactions. The methodologies based on self- confined biological and chemical reactions. This need has contained structures and microfluidic-generated droplets have fuelled the development of a wide range of synthetic already been extensively reviewed 2,6,7 and are only briefly nanostructured (bio)environments, including cell-like addressed here. Instead, we mainly concentrate on the compartments for encapsulating biochemical reactions, emerging tip-assisted methodologies and the materials nanostructured containers for fundamental studies of obtained directly in femtolitre-sized droplets deposited on diffusion, or nanofabricated topological features that regulate 3 surfaces. biomolecular interactions. In addition, the study of naturally occurring chemical processes in confined conditions may shed light onto relevant fields such as the origin of life or Confined reactions in self-contained structures ChemComm atmospheric aerosols that are still poorly understood. 4 Apart from the fundamental studies of (bio)chemical processes and microfluidic channels at the nanoscale, applied chemistry has also benefited from Reactions confined in self-assembled containers the advances made in femtolitre chemistry. In the synthesis of Water-in-oil emulsions are metastable colloids that represent the simplest example of nanocontainers. They are composed of two immiscible fluids, one being dispersed in the other in the shape of femtolitre-sized dropets. 8 These structures have been extensively used to confine biochemical reactions such as the polymerase chain reaction (PCR) 9 and other processes like cell-free protein expression. 10 The resemblance of the lipid bi- This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00 , 1-3 | 1 Please do not adjust margins Please doChemComm not adjust margins Page 2 of 11 ARTICLE Journal Name layer wall of liposomes to cell membranes has favoured their such as metal and metal-oxide nanoclusters, 47,48 as well as to consideration as “artificial cells” 11 and arrays of lipid vesicles perform and study confined enzymatic reactions. 49–51 Self- were suggested as libraries for the simultaneous screening of assembling peptide polynanoreactors have also been multiple analytes. 12 Moreover, the permeability and stability of described and applied to the synthesis of silver the lipid bilayer can be tuned through external stimuli such as nanoparticles.52 electric pulses or temperature changes to trigger the reactions occurring inside the liposomes. 13,14 The use of capsosomes, Reactions confined in droplets generated in microfluidic channels liposomes embedded within polymeric capsules, allowed to and micro/nano-wells perform coupled and parallel enzymatic reactions in confined 15 Microfluidic devices are commonly used to generate and mix conditions by loading the liposomes with different enzymes. droplets under highly controlled environments. This high level These supramolecular organic templates have also been of control is achieved thanks to the generation of microfluidic extensively used for the synthesis of multiple nanoscale solids, 5,16–20 droplets with perfectly controlled and uniform size at the from metallic and ceramic nanoparticles to hybrid 6,53 21 22 cross-stream flow of two immiscible liquids. Due to that, composites or metal-organic particles. The strategy consists microfluidic generated droplets are highly reproducible in mixing two microemulsions (direct or reverse), one synthetic environments that, in turn, provide highly containing the metallic precursor and the other one the so- reproducible conditions and materials. An important added called precipitating agent (Figure 1). Among all the different value of performing femtolitre chemistry in microfluidic nanomaterials synthesized in this way, nanoscale metal- devices is the reduced amount of reagents and solvents that organic materials and coordination polymers have especially are consumed. This is highly important when performing benefitted from this methodology, as it allowed to radically screening studies using precious materials. For this reason, improve the control over the size, shape and crystallinity of the 54–56 23 crystallization of proteins and pharmaceuticals as well as resulting particles. Indeed, since the pioneering work by screening of organic synthetic reactions have been performed Mann and co-workers on the synthesis of Prussian blue 57–59 24 using microfluidic tools. nanoparticles in reverse microemulsions, an increasing Plenty of examples on the use of microfluidics for confined Manuscript amount of reports have appeared that employ this method to biochemical reactions can be found in the literature, going obtain and control the shape and size of Prussian blue 60 61,62 25–28 29–32 from enzyme kinetics to protein expression and single- analogs, metal-organic frameworks (MOFs), or spin- 63,64 33–36 cell studies. However, probably the area in which this crossover polymers among others. Microemulsions have approach has offered more innovative advances is the also been used as nanoreactors to produce polymeric 65 37–40 41,42 synthesis of micro-/nanoparticles, as it allows for a precise nanoparticles and protein nanoparticles. control of the size distribution. 66,67 As an example, gold Beyond synthetic assemblies, natural nanoarchitectures such nanoparticles 68 or nanorods with tunable aspect ratio were as viral capsids and other protein cages have also been used as 69 7,43,44 obtained

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