T he first Nobel Prize for chemistry was awarded in 1901 (to Jacobus van’t Hoff). Up to 2010, the chemistry prize has been awarded 102 times, to 160 laureates, of whom only four have been women (1). The most prominent area for awarding the Nobel Prize for chemistry has been in organic chemistry, in which the Nobel committee includes natural products, synthesis, catalysis, and polymers. This amounts to 24 of the prizes. Reading the achievements of the earlier organic chemists who were recipients of the prize, we see that they were drawn to synthesis by the structural analysis and characterisation of natural compounds.

This paper reviews the current state-of-the-art in the development of highly integrated microfluidic devices for life science applications which have made significant progress in recent years. The strategic approach and the technical challenges in device integration are discussed and practical examples for this integration strategy are presented from different application fields.

A process for synthesising organic azides starting from the corresponding amine is elaborated. It enables the safe handling of a diazo intermediate (stage 1) and its subsequent treatment with sodium azide (stage 2). Accumulation of critical product was prevented by injection of an organic solvent prior to stage 2 followed by instant extraction. In order to minimise all risks arising from potentially formed hydrazoic acid the aqueous product phase was continuously separated and inactivated. This enabled the daily manufacturing of 4.5-6 litre of azide solution in 0.5 M standard concentration.

Nine case-studies of successful implementation of process intensification made up a one-day symposium organized by tNo in Delft, the Netherlands. A summary of these cases yields a guide on how to overcome the technical, economic and cultural hurdles along the way. Process intensification, Pi, promises better value for lower cost, less consumption of feed stock and of energy, and less waste. however, Pi does not appear to become a mainstream activity. “why is that, and what can we do about that?”, opened Arij van Berkel, Director of innovation tNo chemicals, the implementation of Process intensification technologies symposium, in Delft, the Netherlands on April 15.

Significant efforts in studying catalytic processes using small scale flow systems are underway in many laboratories. Microsystems in particular offer the potential to acquire large amounts of data using small material quantities while accessing traditionally difficult experimental conditions. We highlight recent efforts in the field and comment on homogeneous, multi-phase, and solid supported applications. Homogeneous catalytic processes can access chemistries involving unstable intermediates and benefit from low material consumption. The latter has the additional advantage of enabling facile optimization and screening. Multi-phase catalytic processes have been developed that demonstrate catalyst recycling or reaction acceleration due to enhanced mass transfer. We also compare the efficiency of catalysts supported on flow reactor surfaces to packed beds of porous catalyst supports

We present a perspective from our research group on the cyanation of aryl halides and show how recent developments incorporating microwave heating and non-toxic sources of cyanide have opened up simple-to- use methods for the synthesis of aryl nitriles.

Chemical halogenation is a well-established technology often accompanied by hazardous chemicals and low yields. Enzymatic halogenation on the other hand is not used by the industry, even though the first halogenating enzymes were discovered in 1956. There is a trend of increased molecular complexity of halogenated compounds which contain multiple covalently substituted halogen atoms. Allmost all of the incorporations of the halogen atoms in active ingredients must proceed with regioselectivity and often also with stereoselectivity. Biological halogenation can provide this specificity and selectivity. But the technology transfer to large scale manufacturing and established industrial methods are yet to be realized. Recently discovered fluorinases and targeted screening of the marine environment should lead to new industrially useful enzymes.

N,N’,N’’-trialkylated-benzene-1,3,5-tricarboxamides (BTAs) self-assemble via strong, threefold α–helix type intermolecular hydrogen bonding into well-defined, helical, one dimensional columnar aggregates. The introduction of a stereogenic centre into the alkyl side chains of BTAs gives rise to strong Cotton effects in dilute apolar solutions indicating the preference for one helical conformation over the other. Here, we summarise our research on the influence of the position of the stereogenic centre on the aggregate stability and the degree of amplification of chirality in BTAs. In addition, we disclose our results on creating a preferred helical sense in BTA- based supramolecular polymers by introducing H/D isotope chirality into the alkyl side chains of BTAs at the α-position

Contrary to the conventional wisdom that only pure enantiomers are bioactive, natural products with bioactivities are not always enantiomerically pure. For example, tribolure (4,8-dimethyldecanal), the aggregation pheromone of the red flour beetle, is a mixture of all the four stereoisomers in a ratio of (4R,8R)/.(4R,8S)/ (4S,8R)/ (4S,8S)= 4:4:1:1. Stereochemistry- bioactivity relationships among pheromones are not simple but complicated. In the case of tribolure, a mixture with the naturally occurring ratio of the stereoisomers is most active. Neither (R)- nor (S)-sulcatol (6-methyl-5-hepten-2-ol) is behaviourally bioactive as the aggregation pheromone of an ambrosia beetle, whereas their mixture is active. In the case of olean (1,7-dioxaspiro[5.5]undecane), the sex pheromone of the olive fruit fly, its (R)-isomer is active against the males, while its (S)-isomer is active against the females

Rapid enzyme optimization has provided new biocatalysts for the manufacture of chiral amines and alcohols. Where natural enzymes often proved inefficient and labile to process conditions, engineered transaminases and ketoreductases now find widespread use in the commercial manufacture of chiral intermediates. The maturation of biocatalysis via optimization of natural enzymes for function under the non-natural conditions of a chemical manufacturing process is exemplified in this articl

Scale-up in the context of fast moving process development can be problematic. Getting scale-up right requires an understanding of the way in which physical and chemical process parameters interact to determine overall performance. Multiphase systems are particularly difficult. The most common types of scale-up problem at the reaction stage will be shown, and the root causes will be discussed and exemplified. Common root causes are: increases in overall processing time on scale-up, with possible adverse effects on yield and quality; differences in heat transfer capability, which can feed back to increases in cycle time; changes in mass transfer rates, which can impact on reaction time and selectivity; poor dispersion of solids (mass transport), leading to low reaction rates and stalled reactions; and changes in mixing efficiency in homogeneous reactions, with implications for reaction selectivity. A procedure for identification of potential scale-up problems will be described

The viability of using microwaves for industrial energy- efficient processing is assessed. A microwave applicator for petrochemical processing is discussed. A network analyzer was used to study the effects of individual subcomponents on the efficiency. Deflector and reflector subcomponents and their positioning were used to maximize the energy delivered to a process sample

Active ingredient sourcing is often a critical activity in the overall drug development process. The speed at which a source can meet needs is important for both innovator and generic companies. As costs rise around the world, traditional sourcing markets such as Italy have evolved and geographical specializations have emerged. The impact of rising costs on sourcing decisions has motivated some API companies to invest in specialized manufacturing and others to reach into developing markets.

Phosgene and triphosgene are both powerful reagents to access to key speciality chemicals. The hazards associated with the use of phosgene are well known and documented. However, with effective safety management these reagents proved to be highly efficient tools. Triphosgene, regarded by many as a “safer” form of phosgene doesn’t take advantage from the same risk assessment. When the toxicity, stability and reactivity data of triphosgene are evaluated and completed by a calorimetric comparison with phosgene, the data generated confirms the necessity for an exhaustive hazard analysis before implementing the use of triphosgene in any and all chemical processes. A balanced score card approach to risk management versus phosgene highlights and emphasises that for a safe triphosgene management, the best strategy is to confer the synthesis to a phosgene expert.