Juan de M. Muñoz

Microwave-Induced Multiple Functionalization of Carbon Nanotubes

We describe a new synthetic strategy to produce multifunctionalized carbon nanotubes using a combination of two different addition reactions, the 1,3-dipolar cycloaddition of azomethine ylides and the addition of diazonium salts, both via a simple and fast microwave-induced method. The presence of multifunctionality on the SWNTs has been confirmed using the most useful techniques for the characterization of carbon nanotubes. The doubly functionalized SWNTs can be considered potentially useful for many interesting applications.

Preparation of amides mediated by isopropylmagnesium chloride under continuous flow conditions

A safe, green and functional-group-tolerant flow version of the direct amide bond formation mediated by Grignard reagents (the Bodroux reaction) is described. The procedure can be applied to a wide variety of primary and secondary amines and anilines, as well as to aromatic and aliphatic esters. The flow approach leads to improved yields and selectivities in the reaction, which has a sustainable purification procedure and a simple scale-up. This reaction represents an efficient and green alternative to the use of alkylaluminium and metal-catalyzed procedures.

First Example of Alkyl–Aryl Negishi Cross-Coupling in Flow: Mild, Efficient and Clean Introduction of Functionalized Alkyl Groups

The first example of an alkyl-aryl Negishi coupling in a practical, sustainable, and high-yielding process using a silica-supported catalyst in flow is described. Excellent conversions and good functional group compatibility were obtained under very mild conditions. Functionalized alkyl groups were also introduced to provide access to synthetically useful molecules and to demonstrate the versatility of the method. The scalability was assessed, and a throughput of 7.5 mmol/h of processed substrate was achieved. All crude products were free from phosphine derivatives and ready for use in subsequent reaction steps.

Reproducibility and Scalability of Solvent-Free Microwave-Assisted Reactions:From Domestic Ovens to Controllable Parallel Applications

The heating of different parallel arrays in domestic ovens offers the possibility to perform multiple reactions in one irradiation experiment, blending the advantages of microwave heating technology and parallel chemistry. However, they are usually performed without an appropriate temperature control; thus, reproducibility becomes a major issue limiting the application of such reactions. This is exemplified when working at a different scales or using different instruments. For the first time a typical solvent-free reaction described in a domestic oven has been reproduced in monomode reactor, scaled up in a controlled multimode oven and reproduced in parallel, 24 reactions were carried out in a well plate. Parallel reactions were performed in a Weflon multiwell plate to assure identical conditions for each individual reaction. As many reactions under microwave irradiation have been performed in solvent-free conditions, this result opens new possibilities in reproducibility, scalability and combinatorial chemistry and permits to take advantage of many synthetic procedures described in domestic ovens.

First Example of a Continuous-Flow Carbonylation Reaction Using Aryl Formates as CO Precursors

The first continuous flow carbonylation reaction using aryl formates as CO precursor is reported. The reaction is practical, scalable and high yielding. The use of a flow protocol safely allows expanding the scope to activated chlorides, nitrogen heterocycles and to the selective introduction of an ester group in dihalo-derivatives. Further selective reduction of the ester formed to an aldehyde in flow is also described.

Influence of polarity on the scalability and reproducibility of solvent-free microwave-assisted reactions.

Organic reactions performed in the absence of solvent in domestic ovens without appropriate temperature control are generally considered as not reproducible, particularly when different instruments are used. For this reason, reproducibility has historically been one of the major issues associated with Microwave-Assisted Organic Synthesis (MAOS) especially when domestic ovens are involved. The lack of reproducibility limits the general applicability and the scale up of these reactions. In this work several solvent-free reactions previously carried out in domestic ovens have been translated into a single-mode microwave reactor and then scaled up in a multimode oven. The results show that most of these reactions, although not considered as reproducible, can be easily updated and applied in microwave reactors using temperature-controlled conditions. Furthermore, computational calculations can assist to explain and/or predict whether a reaction will be reproducible or not.

Reproducibility and Scalability of Microwave-Assisted Reactions

High-speed microwave synthesis has attracted a considerable amount of attention in the last two decades. Since 2000 the number of publications related to MAOS has increased dramatically. One of the reasons for the increased interest in the use of microwave heating was the introduction, at the dawn of the 21st Century, of dedicated monomode and multimode instruments with appropriate temperature and pressure controls, a development that allows reproducibility of results. However, when the microwave methodology was introduced twenty years ago, most reactions were performed in domestic ovens without appropriate temperature control. In recent years, a number of reports have disclosed the reproducibility of results between monomode and multimode microwave instruments for solution chemistry, the application in parallel and combinatorial chemistry, and some comparisons between homogeneous and heterogeneous systems and reactions performed in closed or open vessels. In the same way, it has been shown that solvent-free reactions can be updated and applied in microwave reactors and the influence of the polarity on the reproducibility of these processes has been highlighted. Furthermore, computational calculations can assist in explaining and/or predicting whether a reaction will be reproducible or not. Possible approaches to scale-up microwave-assisted reactions include continuous-flow reactors, small-scale batch stop-flow protocols or large-scale single-batch reactors. However, the scalability of microwave-induced processes represents an important obstacle due to numerous factors, but principally owing to increased heat loss, changes in absorption, limited penetration depth of the radiation into the reaction medium (only a few centimetres at 2.45 GHz) and the additional reflection of the microwaves. Such intrinsic complications have prevented the use of microwave reactors for volumes larger than a few litres, thus inhibiting the use of this approach for the production of larger quantities of material. Alternatively, some researchers and microwave manufacturers have explored the potential of continuous flow microwave systems. Such an approach offers many advantages in terms