Our department has pioneered the use of continuous flow reactors by synthetic organic chemists. Continuous flow reactor systems offer significant advantages when performing reactions which are mixing controlled, or where heat- and mass-transfer are important. These properties derive from the exceptionally high surface-to-volume ratios accessible in continuous flow reactors. It is simple to scale-up microreactor processes either by numbering-up reactors or running the reaction for extended duration. We utilize both commercially available and internally developed systems (Figure 1), ranging from microliter-volume etched silicon chips to milliliter-volume tubing reactors. Our work with these systems has exemplified the broad scope of their application, not only in traditional organic chemistry, but also in the preparation of polymers, nanoparticles and functionalized biomolecules.

Reactions of Hazardous and High-Energy Species

Continuous flow reactor systems provide ideal conditions for the detailed study of the formation and subsequent transformations of high-energy compounds. High temperature and pressure conditions can be achieved with improved safety and efficiency compared to batch processes; superheating of solvents is simple and hazardous reagents can be more safely handled by minimizing their concentration at the point of reaction. Additionally, the short residence times accessible in microreactors often reduce the potential for side reactions of highly reactive species. In addition to safe and efficient amidations of esters using pyrophoric AlMe₃ [1], radical reductions [2] and fluorinations with the thermally-unstable fluorinating agent DAST [3], we have studied the continuous flow generation of nitrenes via thermolysis of azides [4]. Continuous flow thermolysis of 3-aryl-2-azidoacrylates to give indole 2-carboxylates, previously requiring sealed tube conditions and extended heating of potentially explosive azides, has been successfully performed in our laboratory (Figure 2). We applied this method to the synthesis of a variety of heterocycles, with exceptionally high productivity.

Polymers

Classical emulsion polymerization produces high molecular weight polymers at high rates of polymerization, rendering this process very attractive for industrial applications. Recent improvements in the regulation of reaction conditions, safety and quality control have prompted efforts toward miniaturization, embracing advances in microfluidics. In collaboration with the MPIKG Colloid Department and the ETH Zürich, we have developed a continuous flow emulsion polymerization process using phosphine oxide photoinitiators [5]. Polymer nanoparticles of very high molecular weights were formed by a novel mechanism (Figure 3). Incorporation of phosphine oxide units into the polymer backbone induces repeated, snowballing radical generation upon irradiation where polymer-associated mono- and diradicals are created and do not terminate instantly. This process dramatically increases the radical polymerization rate and generates long polymer chains with ultrahigh molecular weights. The avalanche-like formation of radicals that occurs inside the latex particle also causes an enormous increase in the average number of growing polymer chains per particle. A stochastic model was used to simulate snowballing kinetics and quantitatively rationalize the polymerization process.

Controlled free radical polymerizations (CRP) have evolved over the last 20 years into very useful and widely applied techniques for polymer synthesis, combining the excellent control of traditional ionic living polymerizations with robust conventional free radical polymerizations. Among these techniques, reversible addition fragmentation chain transfer (RAFT) represents the most versatile and facile method. In contrast to generally fast free radical polymerizations, the controlled living process requires longer reaction times. Heating by microwave irradiation can considerably shorten the reaction times, but the scale-up of microwave reactions is difficult. We developed the first homogeneous RAFT polymerizations in a continuous flow reactor [6]. The polymerization is considerably faster when compared to batch reactions (Figure 4). Thermoresponsive PNIPAM with apparent molecular weight of 20 kDa was obtained within minutes in flow, instead of hours in batch. The continuous flow polymerization exhibited similar kinetics as under microwave irradiation, but with the advantage of being readily scalable.

Nanomaterials

The need for large quantities of monodisperse semiconductor nanocrystrals, (quantum dots – QDs), and the difficulty of their preparation via traditional batch techniques has prompted us to explore the use of continuous flow microreactors [7]. Taking advantage of the precise temperature control and efficient heat transfer of continuous flow microreactors allowed reduction of the reaction temperature from 300 °C to 160 °C. Lower temperature prevented the fast nucleation and generation of large non-homogeneous nanocrystals. By varying the residence time between 3 and 30 minutes, different sized CdSe and CdTe nanoparticles were obtained. The different size leads to different physical properties, especially the luminescence maxima (Figure 5). Characterization of the different QDs by transmission electron microscopy (TEM) revealed highly crystalline, monodisperse, cubic nanoparticles. A microreactor was also used for the preparation of carbohydrate-functionalized QDs under mild liquid-phase conditions for the investigation of specific carbohydrate-lectin interactions.

Functionalization of Biomolecules

Dendronized polymers are multivalent, flexible systems that can bend to adapt to the environment of a pathogen surface and optimize binding to bacterial carbohydrate receptors. Functionalization of these polymers is challenging as the coupling reaction must be selective and high yielding, whilst not contaminating the end product. To address this challenge, we explored the usefulness of photochemical [2+2] cycloaddition, which can be carried out in water using inexpensive starting materials; it is pH independent and circumvented the use of heavy metals or other reagents that contaminate the polymer product [8]. Traditionally, photochemical reactions have been poorly scalable. Using a continuous flow photochemical reactor allowed us to develop an efficient, fast and readily scalable synthetic route to dendronized polymers. We are continuing to investigate the continuous flow conjugation of biomolecules with carbohydrates.

Reaction Optimization and System Development

In both industrial and academic settings, much of the effort spent by synthetic organic chemists is consumed searching for optimal reaction conditions to achieve a particular transformation. A key advantage to performing chemistry in microreactor systems is the speed with which mechanistic data can be obtained and conditions altered. Thus, only small quantities of reagent are required for the optimization process. We have developed screening platforms for the systematic study of glycosylation reactions: a transformation of critical importance for our department [9]. By combining automated screening with inline analysis and design-of-experiment algorithms, we are now developing completely automated optimization systems. We work closely with industrial partners in this area, using our experience in continuous flow microreactor technology for rapid process development.

F. Bou Hamdan, C. Diehl, J. C. Klein, P. Laurino, F. Lévesque, X.-Y. Mak, A. G. O’Brien and Y. Suzuki.

References:

[1] Gustafsson, T., Pontén, F., Seeberger, P. H.: Trimethylaluminium mediated amide bond formation in a continuous flow microreactor as key to the synthesis of rimonabant and efaproxiral, Chem. Commun. 1100 (2008).

[2] Odedra, A., Geyer, K., Gustafsson, T., Gilmour, R., Seeberger, P. H.: Safe, facile radical-based reduction and hydrosilylation reactions in a microreactor using tris(trimethylsilyl)silane, Chem. Commun. 3025 (2008).

[3] Gustafsson, T., Gilmour, R., Seeberger, P. H.: Fluorination reactions in microreactors, Chem. Commun. 3022 (2008).

[4] O’Brien, A., Lévesque, F., Seeberger, P. H.: Continuous flow thermolysis of azidoacrylates for the synthesis of heterocycles and pharmaceutical intermediates. in press (2010).

[5] Laurino, P., Hernandez, H. F., Bräuer, J., Grützmacher, H., Tauer, K., and Seeberger, P. H.: Snowballing Radical Generation Leads to Ultrahigh Molecular Weight Polymers. Under review (2010).

[6] Diehl, C., Laurino, P., Azzouz, N. Seeberger, P. H.: Accelerated Continuous Flow RAFT Polymerization. Macromolecules, in press (2010).

[7] Kikkeri, R., Laurino, P., Odedra, A., Seeberger, P. H.: Synthesis of Carbohydrate-Functionalized Quantum Dots in Microreactors. Angew. Chem. Int. Ed. 49, 2054 (2010).

[8] Laurino, P., Kikkeri, R., Azzouz, N., Seeberger, P. H.: Detection of Bacteria Using Glyco-dendronized Polylysine Prepared by Continuous Flow Photo-functionalization. Nano Lett. in press (2010).

[9] a) Seeberger, P. H., Geyer, K., Trachsel, F.: Microreactor system and method for operating such microreactor system, Eur. Pat. Appl. EP 2153892A1 (2010). b) Geyer, K., Seeberger, P. H.: Optimization of glycosylation reactions in a microreactor, Helv. Chim. Acta 90, 395 (2007). c) Ratner, D. M., Murphy, E. R., Jhunjhunwala, M., Snyder, D. A., Jensen, K. F., Seeberger, P. H.: Microreactor-based reaction optimization in organic chemistry-glycosylation as a challenge. Chem. Commun. 578 (2005).