During the last decade, the application of micro- and mesofluidic continuous flow conditions in laboratory scale has been developed into a powerful enabling technology for synthetic chemists.74 Several research groups both in the academic world and in the industry are currently in the process of exploring the limitations and possibilities of continuous flow conditions in organic synthesis. Whereas a “do it yourself” mentality has served well in the early development of continuous flow methodologies, the 2000s have seen the launch of commercial laboratory scale equipment that can be used in a highly modular fashion.75 These technologies range from microfluidic chips to fully integrated reactor systems which are usually based on commercial HPLC equipment, with specific modifications to answer specific needs. A standard example is the ThalesNano H-Cube® flow hydrogenator, in which a solution of the substrate is pumped through a cartridge filled with an immobilized hydrogenation catalyst, e.g. Pd/C.76 Hydrogen is produced on demand in an integrated electrolytic cell and mixed into the substrate stream before the cartridge, thus circumventing the problem of storing and handling hazardous gases (although at a nontrivial energy cost).
Below we shall consider the benefits and disadvantages of carrying out organic synthesis in continuous flow conditions using microreactors.
3.1.1 Benefits and Disadvantages of Continuous Flow Conditions
The mechanism of a reaction obviously does not change when transferred from batch to flow systems. However, the differences in mass and heat transfer properties of the reactor system may have a profound effect on the rate and selectivity of the reaction in question. Some recent reviews shed light on these issues in a highly lucid fashion.74e,f Overall, one of the greatest advantages of continuous flow conditions is the precise control over reaction parameters due to the enhanced mass and heat transfer properties.
55 One of the most important issues of carrying out a chemical reaction is the proper and efficient mixing of reagents. In microreactors (reactor channel diameter 10-500 Pm), laminar flow conditions usually exist (Re <2000), and mixing of reagents takes place via diffusion. It has been calculated that for a molecule of typical diffusivity, it takes 30 seconds to achieve complete mixing in a reaction channel of 400 Pm i.d. With specifically fabricated micromixers, this mixing time can be reduced to the order of 10 milliseconds. This is highly beneficial for extremely fast reactions for which the rates are controlled by mass transfer. For reactions in which substrates may react further than to the desired product, fast mass transfer usually results in better selectivities.77
The volume-area relationship of continuous-flow reactors is usually very high, on the order of 5000-50000 m3/m2, which makes heat transfer into and from the reaction system very efficient, depending on the thermal conductivity of the reactor material. This is highly beneficial for reactions that release powerful exotherms, such as lithiation reactions. The group of Yoshida has made significant contributions in this field, carrying out highly exothermic and fast lithium-halogen exchange reactions with residence times of less than a second in a cooled glass chip reactor.78 Even though the released energy per reactant mole is impressive, in a microfluidic environment there are only small amounts of reacting materials at a given moment, and hence the exotherm may be compensated by the high thermal conductivity.
The contained environment and relative ease of pressurizing a continuous flow reactor enables the superheating of reaction solvents above their boiling point in atmospheric pressure in a safe manner.74g,79 Thus reactions that are accelerated by high pressures (reactions with negative volume of activation/volume change) and temperatures, such as Diels-Alder reactions, may be beneficially transferred to continuous flow conditions.80 Unstable, hazardous and noxious reagents and intermediates are likewise contained in the reactor system, and thus carrying out certain reactions may be significantly safer.81
The most obvious problem of microfluidic technologies lies in the intrinsic micro aspect.
Reaction channels that are usually less than 0.5 mm in diameter are highly prone to clogging by salts and products crystallizing out from a reaction mixture.82 At worst this can lead to powerful pressure buildup in the system and subsequent rupturing of the reactor vessel, coil or chip, or other damage to the pumps and valves. When dealing with the issue of precipitation and clogging, the reaction conditions in question usually need to be modified to suit the microfluidic system. Lowering the concentration and changing the solvent system are obvious
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methods, which however may lead to suboptimal performance of the reaction and increased amounts of solvent waste.
When continuous flow conditions are applied to multistep synthesis, reaction monitoring and coordination of further steps may become problematic (so-called “third stream problem”). In tubular reactors where the fluid flow is laminar there is always some diversion from an ideal plug-flow, which leads to axial dispersion and a bell curve shaped reactant concentration with respect to time and reactor length.83 The injection of subsequent reactant streams has to be coordinated so that there is minimum loss of substrates. In a continuous process this is an issue only in the beginning, before reaching an equilibrium state. If a multistep process is performed in a plug flow manner (e.g. in discovery chemistry for pharmaceuticals), there is a need for robust in line monitoring and automation so that the injection of further reactant streams may be triggered when a desirable concentration of product is observed.
3.1.2 General Strategies for Continuous Flow Synthesis
Transferring a reaction from batch to continuous flow conditions often requires a change in the overall philosophy of chemistry.84 As will also be shown in Chapter 4, homogeneity of the reaction becomes a major consideration and affects directly reactant concentration in solution.
In line quenching and purification of the reaction mixture is another important consideration.
Solid supported reagents, such as acidic and basic resins have been widely used for both purposes. However, solid supported reagents suffer from the obvious drawback that they have a specific loading capacity, and for large scale synthesis, which in flow conditions translates to long operating time, such reagents should periodically be either replaced with new material or regenerated with a washing sequence.
Catalysis in continuous flow conditions can be approached with several strategies.
Homogeneous catalysis may be carried out in continuous flow conditions in an analogous manner to flask chemistry just by injecting the catalyst into the reaction stream.85 Product isolation and catalyst separation then become the crucial issues. These may be solved by scavenging reagents, catch and release techniques (of either catalyst or product), or by incorporating a reactive tag in the catalyst structure which enables further operations.
Immobilizing a catalyst on a solid support is one of the ideal solutions, but it is usually associated with both benefits and disadvantages.86 Immobilization forces reactions to take place on the catalyst surface, which usually has a detrimental effect on reaction kinetics.
Another adverse kinetic effect may be caused by the improper porosity of the catalyst, since
57 the diffusion time for substrates to reach a catalytic site within the support matrix is lengthened. If the porosity is suboptimal, some of the catalyst might be completely occluded and cannot come into contact with the substrates. In the case of asymmetric catalysis, the steric effects caused by the structure of the solid support may also deteriorate catalyst selectivity. Further issues are e.g. the mechanical, thermal and chemical stability of the support and its swelling properties in different solvents. Most of these issues depend on the synthesis of the solid support (degree of cross linking in a polymer, polymer beads vs.
monolithic column, sol-gel synthesis of SiO2 with controlled pore size, etc.) and the method of catalyst immobilization (co-polymerization, grafting, etc.). This is a science in itself and beyond the scope of this thesis.
The highly automated synthesis of racemic oxomaritidine illustrates several key issues and strategies in flow chemistry (Scheme 32).87 A solution of bromide 110 in 1:1 CH3CN:THF was passed through an ion exchange resin to give the azide 111, which was subsequently immobilized as the corresponding iminophosphorane on a butylphosphine functionalized resin. Aldehyde 113, obtained by oxidation of the corresponding alcohol by passing a THF solution through a column packed with immobilized tetra-N-alkylammonium perruthenate, was pumped with 111 through a phosphine column to yield the aza-Wittig product 114. The imine was then reduced to the amine 115 with a flow hydrogenator equipped with a 10% Pd/C catalyst cartridge. After a manual solvent exchange from THF to CH2Cl2, the amine was trifluoroacetylated in a chip reactor, and then passed through a column loaded with a PIFA- functionalized resin to effect the oxidative phenolic coupling to give the intermediate 117.
Treatment of 117 with a strongly basic resin in the presence of a 4:1 MeOH:H2O side stream hydrolyzed the amide, which then underwent a spontaneous conjugate addition to give racemic oxomaritidine 118 in an overall yield of 40%. Most impurities were scavenged by the basic resin, and the natural product was obtained with excellent purity.
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Scheme 32. Continuous flow synthesis of racemic oxomaritidine
The time taken by the synthesis was 8 hours, which is significantly faster than performing the same synthesis with traditional methods, albeit the scale of the flow synthesis is rather small.
Planning and optimizing each step of a multistep synthesis like oxomaritidine obviously is quite time consuming. However, providing that a great number of known robust transformations can be carried out in flow conditions, chemists should be able to perform multistep flow syntheses routinely in the near future. The synthesis of oxomaritidine also illustrates one of the greatest benefits of continuous flow systems. With each step telescoped into the next one, the number of required unit operations is reduced significantly, since there are no extraction or chromatography steps included, with only two evaporation steps. This equates directly to reducing waste and saving consumables such as solvents and SiO2, but even more importantly, time and manpower.
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