Recently, application of the flow technologies for the preparation of fine chemicals, such as natural products or Active Pharmaceutical Ingredients (APIs), has become very popular, especially in academia. Although pharma industry still relies on multipurpose batch or semibatch reactors, it is evident that interest is arising toward continuous flow manufacturing of organic molecules, including highly functionalized and chiral compounds. Continuous flow synthetic methodologies can also be easily combined to other enabling technologies, such as microwave irradiation, supported reagents or catalysts, photochemistry, inductive heating, electrochemistry, new solvent systems, 3D printing, or microreactor technology. This combination could allow the development of fully automated process with an increased efficiency and, in many cases, improved sustainability. It has been also demonstrated that a safer manufacturing of organic intermediates and APIs could be obtained under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with minimum risk. In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of organic molecules which found application as APIs, especially highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies, and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufacturing. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions, will be also presented, and most significant examples will be described; our purpose is to illustrate all of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.

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Pebbles is a user-friendly software program which implements an accurate, unbiased, and fast method to measure the morphology of a population of nanoparticles (NPs) from TEM micrographs. The morphological parameters of the projected NP shape are obtained by fitting intensity models to the TEM micrograph. Pebbles can be used either in automatic mode, where both fitting and validation are reliably carried out with minimal human intervention, and in manual mode, where the user has full control on the fitting and validation steps. Accuracy in diameter measurement has been shown to be ≲1%. When operated in automatic mode, Pebbles can be very fast. The effective speed of 1 NP s⁻¹ has been achieved in favorable cases (packed monolayer of NPs). Since Pebbles is based on a local modeling procedure, it successfully treats cases such as low contrast NPs, NPs with significant diffraction scattering, and inhomogeneous background which often make conventional thresholding procedures fail. Pebbles is accompanied by PebbleJuggler, a software program for the statistical analysis of the sets of best-fit NP models created by Pebbles. Effort has been devoted to make Pebbles and PebbleJuggler the most user-friendly and the least user-tedious we could. Pebbles and PebbleJuggler are available at http://pebbles.istm.cnr.it.

The manufacturing of a three‐dimensional product from a computer‐driven digital model (3D printing) has found extensive applications in several fields. Additive manufacturing technologies offer the possibility to fabricate ad hoc tailored products on demand, at affordable prices, and have been employed to make customized and complex items for actual sale. However, despite the great progress and the countless opportunities offered by the 3D printing technology, surprisingly a relatively limited number of applications have been documented in organic chemistry. This Minireview will focus specifically on the exploitation of additive manufacturing technologies in the synthesis of organic compounds, and, in particular, on the use of 3D‐printed catalysts and 3D printed reactors, and on the fabrication and use of 3D printed flow reactors.

Octahedral monodisperse R-MnS and MnO nanoparticles have been synthesized by decomposing manganese oleate and elemental sulfur in octadecene at high (250-320 °C) temperature. The chemical composition of the obtained NPs depends on the Mn:S ratio in an unexpected way. Pure R-MnS NP samples are obtained when S:Mn g 2:1, whereas pure MnO NPs require S:Mn e 0.6. Variation of several parameters (concentration of sulfur, heating rate and aging temperature and time) resulted in a R-MnS NP size interval of 11-14 (from Mn monooleate) and 18-30 nm (from Mn dioleate). For MnO NPs only, size control is also possible by addition of free oleic acid (14-24 nm). Analysis of TEM tilting experiments and electron diffraction shows that both R-MnS and MnO nanoparticles have octahedral shape and spontaneously form ordered arrays with strong texture in the {111} direction. Measurement of the magnetic properties showed that R-MnS nanoparticles consist of an antiferromagnetic core and a ferromagnetic-like shell that are exchange coupled below the blocking temperature of the shell (23 K for 29 nm R-MnS NP).

The immobilization of the catalyst on a support with the aim of facilitating the separation of the product from the catalyst, and thus the recovery and recycling of the latter, can be regarded as an important improvement for a catalytic process. However, a system where a catalyst must not be removed from the reaction vessel is even more attractive: in continuous flow methods the immobilized catalyst permanently resides in the reactor where it transforms the entering starting materials into the desired products. The retention of the catalytic species inside the reaction vessel can be achieved by different techniques ranging from ultrafiltration through a M W-selective membrane to immobilization on different supports. In this review we will discuss the most significant examples of stereoselective reactions promoted by immobilized chiral catalysts and performed under continuous flow conditions, with particular attention to the more recent contributions of the last few years.

Radical copolymerisation of divinylbenzene and a properly modified enantiomerically pure imidazolidinone inside a stainless steel column in the presence of dodecanol and toluene as porogens afforded the first example of a chiral organocatalyst immobilized onto a monolithic reactor. Organocatalyzed cycloadditions between cyclopentadiene and cinnamic aldehyde were performed under continuous-flow conditions; by optimizing the experimental set up, excellent enantioselectivities (90% ee at 25 [degree]C) and high productivities (higher than 330) were obtained, thus showing that a catalytic reactor may work efficiently to continuously produce enantiomerically enriched compounds. The same catalytic reactor was also employed to carry out three different stereoselective transformations in continuo, sequentially, inside the chiral column (Diels-Alder, 1,3-dipolar nitrone-olefin cycloaddition, and Friedel-Crafts alkylation); excellent results were obtained in the case of the former two reactions (up to 99% yield, 93% ee and 71% yield, 90% ee, at 25 [degree]C, respectively). In addition to simplify the product recovery, the monolithic reactor performed better than the same supported organocatalyst in a stirred flask and could be kept working continuously for more than 8 days

3D-printed flow reactors were designed, fabricated from different materials (PLA, HIPS, nylon), and used for a catalytic stereoselective Henry reaction. The use of readily prepared and tunable 3D-printed reactors enabled the rapid screening of devices with different sizes, shapes, and channel dimensions, aimed at the identification of the best-performing reactor setup. The optimized process afforded the products in high yields, moderate diastereoselectivity, and up to 90 % ee. The method was applied to the continuous-flow synthesis of biologically active chiral 1,2-amino alcohols (norephedrine, metaraminol, and methoxamine) through a two-step sequence combining the nitroaldol reaction with a hydrogenation. To highlight potential industrial applications of this method, a multistep continuous synthesis of norephedrine has been realized. The product was isolated without any intermediate purifications or solvent switches.