WO2002049737A1

WO2002049737A1 - Use of a microreaction channel with a piezo element

Info

Publication number: WO2002049737A1
Application number: PCT/EP2001/013872
Authority: WO
Inventors: Hanns Wurziger; Guido Pieper; Michael Schmelz; Norbert Schwesinger
Original assignee: Merck Patent Gmbh
Priority date: 2000-12-18
Filing date: 2001-11-28
Publication date: 2002-06-27
Also published as: DE10063027A1; AU2002227951A1; TW508267B

Abstract

The invention relates to a construction of a microchannel system in a silicium wafer connected to a ceramic bimorph. The invention also relates to the use of said construction for carrying out chemical reactions.

Description

Use of a microreaction channel with a piezo element.

The present invention relates to the construction of a microreaction channel system in interconnected silicon wafers, which is connected to a ceramic bimorph or a piezo element. The invention also relates to the use of this construction for performing phase transfer catalytic reactions.

Phase transfer reactions between two immiscible phases have particular problems for the person skilled in the art in comparison to reactions in homogeneous phase, which result from the fact that a reaction only starts when the system adds a small amount of a catalytically active substance which unites one the reactants, usually an anion extracted through the interface from one phase to the other. Such catalytically active substances serve as solubilizers. But not only the activity of the catalytically active substance is decisive for the speed of such reactions, but in particular the effective size of the interface available for phase transfer is also decisive. To achieve this, the phases in the reactors are brought into contact at high stirring speed.

Although phase transfer catalysis is usually distinguished by a high selectivity, the phase transfer catalysts used are usually unstable at higher temperatures. For example, quaternary ammonium or phosphonium salts decompose at temperatures from 120 to 150 ° C. Others even decompose at lower temperatures. Separation, recovery and use can also be problematic. Factors such as price, toxicity and disposal of contaminated chemicals and the high energy requirements are also often problems.

The object of the present invention was therefore to provide both a system and a method by means of which phase transfer reactions can be carried out in a simple and inexpensive manner without causing the disadvantages indicated above. Since all the reactants in the reactions described above are in solution, miniaturized flow-through reactors were investigated for their applicability due to their outstanding mixing properties.

A particular advantage of these reactors is that there are only small amounts of reaction mixture in the reactor at all times. This type of reactor is therefore suitable for reactions that have to be carried out using particularly aggressive or environmentally hazardous chemicals.

• 10

Experiments have shown that, provided that all substances remain in the dissolved liquid phase and do not fail during the passage through the microsystems, phase transfer reactions can be carried out in miniaturized flow reactors.

15 For the experiments carried out, appropriate reactors were used, which can be produced with the aid of technologies used in the production of silicon chips (Schwesinger, N., Marufke, O., Stubenrauch, M., Hohmann, M. and Wurziger , H. in MICRO SYSTEM Technologies 98, VDE-Verlag GmbH, Berlin and Offenbach 1998). Prefers

Such reactors are produced by connecting thin silicon structures to one another. However, it is also possible to use comparable reactors which are made from other materials which are inert to the reaction media. What these miniaturized reactors have in common is that they have very thin channels, which in themselves are very light

25 tend to clog due to particles contained or formed in the reaction solution.

Initial attempts to carry out phase transfer reactions in the miniaturized flow reactors commonly used showed that this is fundamentally possible. However, these attempts led to unsatisfactory yields. A solvent system which consists of an aqueous solution and a solution in which dichloromethane serves as solvent is usually used to carry out corresponding reactions. Using such a system, it was found that although there was very good mixing in the micromixer, the mixture as soon as it left the mixer and into the subsequent dwell section in Long capillary occurs, the phases separate and independent drops are conveyed through the capillaries. The yields obtained were correspondingly low under these conditions.

Surprisingly, this problem has now been solved and the reaction results have been considerably improved by connecting the actual micro-reactor to a miniaturized flow-through reactor which is additionally equipped with a piezo element.

1 shows a drawing of such a piezo element with its electrical connections in connection with a silicon chip.

The special design of the flow reactor used is a channel system of 30 cm length produced by anisotropic etching in silicon with a total volume of 80 μL with external dimensions of 2.7 x 4.1 x 0.1 cm, on which a ceramic one Bimorph was glued on to generate sound.

Completely surprisingly, it was found that with this system - in conjunction with a silicon micromixer which works according to the principle described in DE 19511603 A1 - reactions in immiscible fluid phases can be carried out with significantly better results. In this way, phase transfer-catalyzed N-, C-, 0- and S-alkylations and etherifications can be carried out in flow without having the disadvantages listed above. The phases are intensely mixed by the introduction of ultrasound energy, forming large interfaces over which the mass transfer is accelerated very quickly, without the phases having to be brought into contact with one another with high stirring speed and high energy consumption, as is customary. Provided that all substances remain in the dissolved liquid phase during the passage through the microsystems and do not precipitate out, all alkylations and etherifications per se can be carried out with the reagents and solvents customary in the literature:

Alkyl, allyl, propargyl, aryl ethyl halides and sulfonates as alkyl lierungsmittel

Chlorinated hydrocarbons as water-immiscible solvents

aqueous alkalis as bases

tertiary ammonium compounds as catalysts

The alkylations carried out with the combined microsystem according to the invention lead to very good to excellent yields in comparison with known processes.

The experiments have found that the selectivity of these reactions can be influenced or optimized by varying various parameters, such as concentration, temperature or residence time.

Carrying out the alkylations and etherifications in the microfluid systems according to the invention has advantages in comparison to the reaction systems usually used in the form of better mass and heat transport, improved control of the reaction times and increased safety when dealing with dangerous substances. This is due in particular to the very small amounts of reagent in the system. The very good mixing of the reagents and the continuous procedure contribute significantly to better control of the reaction conditions.

Optimization tests on model reactions have shown that these reactions can be carried out continuously with good to very good product yields using the miniaturized flow reactor with piezo element according to the invention. In this way, very small quantities can be used at any time. Sufficient product can be obtained at the same time per unit of time, since on the one hand, in contrast to a batch process, there are no idle times and, on the other hand, several reactions can be carried out in parallel in different reactors due to the small space and investment requirements for a single microreactor. Advantageously, it is also possible in a simple manner to carry out the alkylation and etherification process according to the invention under protective gas conditions, especially since this can be better achieved with the small dimensions of the system than in large conventional plants.

The piezo element shown in FIG. 1, which has been used for the tests carried out, has a frequency control which enables an adjustment in the range from 750 to 16000 Hz.

In the method according to the invention, different frequencies can be set in this way, depending on the reaction system used, in order to achieve an optimal result. For example, the influence of the set frequency on achievable yields on the two-phase system aqueous NaOH solution / salicylaldehyde derivative and catalyst in dichloromethane was investigated. 2 shows the schematic structure of the miniaturized system used.

If 5-bromosalicylaldehyde was reacted with allyl bromide in the presence of a catalyst in dichloromethane in a miniaturized pilot plant with aqueous sodium hydroxide solution at room temperature at the minimum excitation frequency of 750 Hz, only a product yield of 2.72% was achieved. Even a slight increase in frequency increased to 9.26%. By further increasing the frequency, the yield rose to 12.7%. In comparison, no product was obtained during a reaction time of one minute without the influence of the excitation. The latter can be seen as clear evidence of the influence of ultrasound excitation. The tests carried out also showed that there is an optimal frequency setting for an optimal result under the given reaction conditions. If the frequency was increased to 16 kHz under otherwise identical conditions, no product was formed during the reaction time of one minute. By controlled change in frequency under otherwise unchanged conditions, the optimal frequency can be determined for a specific reaction, such as. B. is shown in Fig. 3.

Further tests confirmed that the yield is influenced in addition to the frequency and the residence time in the reactor system. It was found, that with an optimally set frequency, a yield can only be achieved with a sufficient dwell time, which can no longer be increased under the given reaction conditions. In the reaction system tested, the optimal residence time was 4 minutes. Longer dwell times did not lead to an increase in yield.

Experiments with other starting compounds showed that the system according to the invention can be used for a wide variety of alkylations and etherifications.

Compounds which are liquid at room temperature are preferably used as reactants. However, it is also possible to heat and liquefy the starting materials in the temperature-controlled microreactor before mixing. In such a case, however, it is more advantageous to dissolve a solid starting material in a solvent which is inert in the reaction. Suitable solvents for this purpose are those from the group of water-immiscible hydrocarbons, chlorinated hydrocarbons, such as. B. dichloromethane, trichloromethane and carbon tetrachloride, it being assumed that there is only sodium hydroxide in the aqueous phase and the catalyst used in the second phase.

It is readily possible for the person skilled in the art to choose suitable solvents adapted to the reaction to be carried out on the basis of available material data.

To carry out the process according to the invention, the reactants are initially introduced in liquid or dissolved form and, under the conditions described, are reacted with one another in the miniaturized reaction system under the influence of the ultrasound energy introduced. For this purpose, the solutions are prepared in such a way that the molar ratio of the reactants to one another is in the range from 1: 2.1 to 1: 3. Solutions are preferably used in which the ratio is between 1: 2.3 to 1: 2.7, in particular those with an educt ratio of 1: 2.5. The chosen ratio has to be matched to the reactivity of the reactants used and the optimal value can therefore be very different. However, not only the molar ratio of the starting materials to one another has an influence on the result. As described, the external conditions in the microreaction system have a decisive influence on the result. These factors are flow rate, energy introduced by ultrasound, temperature, the catalyst used, but also the pressure generated in the microreactor.

During test trials with the model media, different

Flow rates of 40 to 160 ul / min, which led to residence times in the overall system of one to four minutes, worked. In the case of reactions with other starting materials, completely different residence times can result in optimal. The same applies to the setting of an optimal ultrasound frequency for energy input.

The yield achieved is generally significantly influenced, in particular, by the reaction temperature. While the model reaction at room temperature already leads to good results, it may be necessary to carry out other comparable reactions at higher temperatures. For this purpose, a heatable microreactor known from the literature can be used, which is connected to a miniaturized flow reactor with piezo element described above. In this way, corresponding reactions which only take place at a higher temperature can also be carried out in the system according to the invention. In such cases, the product yield can be optimized by variation of the flow rate as well as the temperature and the ultrasound frequency and, if necessary, the formation of by-products can also be reduced. It is possible for a person skilled in the art to optimally set these parameters in accordance with the respective reaction.

All attempts to carry out this reaction in the given flow reactor under otherwise constant process conditions, but with higher flow rates than that which led to maximum product yields at room temperature, were associated with reduced product yields, which is due to the fact that the reaction was evident due to the reduced residence time in the reactor cannot be ended.

To increase the amount of product achieved per unit of time, it is also possible for a person skilled in the art to vary the miniaturized flow reactor used to extend the residence time while at the same time to achieve reaction conditions, which enables him to increase the flow rate and at the same time to increase the achievable product quantity. However, it is also possible to pass the reaction mixture through two or more miniaturized flow reactors connected in series, so that at an increased flow rate the

Reaction ended and thus the amount of product achieved can be increased.

A variation of the miniaturized flow reactor used also means that, on the one hand, an increased number of the individual structures making up the flow reactor can be connected to one another, as a result of which the length of the thin channels located in the flow reactor is increased. It is readily possible for the person skilled in the art to achieve an extension by changing the position of the channels in the structures connected to one another. Various solutions to this problem are known from the patent literature.

To carry out the method according to the invention, miniaturized flow reactors are particularly suitable whose channels have a diameter of at least 25 μm. It is even possible to use microreactors whose channels have a diameter of 1 mm, since the advantages described above can also be demonstrated here.

If the alkylation or etherification is carried out in a flow-through reactor with a larger diameter of the flow-through tubes, the flow-through rate must be adjusted, as already indicated above, so that the residence time of the reaction mixture in the reactor is so long that the desired reaction can be ended, and one optimal product yield can be achieved. To end the reaction, it is also possible to connect the outlet channel of the static micromixer through which it flows with a correspondingly long, temperature-controlled capillary with a suitable diameter, provided that this channel can also be excited by ultrasound. After flowing through this capillary, the product formed can be worked up in a conventional manner.

It is crucial for the choice of the miniaturized flow reactor to be used that the reaction mixture is uniformly mixed intensively in each volume element,

- The canals are so wide that an unhindered flow is possible without an undesirable pressure building up or that they become blocked by inhomogeneities,

the length and the diameter of the tubules through which flow takes place ensure a sufficient residence time for the reaction to end,

- A uniform temperature control is guaranteed in every volume element of the reactor, - Dense and secure connection options for supply and discharge of liquids, if necessary also for other equipment for reaction control or for analysis purposes,

a tight connection of the individual parts or structures forming the microreactor is provided both inside and outside, so that the channels carrying liquid are separated from one another and no liquid can escape to the outside,

- Easy handling is guaranteed in the event of malfunctions

- There is a simple connection option for the ultrasound source to the miniaturized flow channel adjoining the microreactor.

For a better understanding and clarification of the present invention, model examples are given below with reference to a model reaction which are within the scope of the present invention but are not suitable for restricting the invention to these examples. As already mentioned above, within the scope of the present invention are also to be understood those embodiments of the invention which are carried out using static micromixers and miniaturized flow reactors which are also known to the person skilled in the art, but the flow reactors used for producing larger amounts of product in can allow larger flow rates for the same unit of time and furthermore ensure both uniform temperature control and homogeneous mixing in each volume element of the reactor, or allow an input of ultrasonic energy in another way. example

catalyst

aqueous NaOH

5-Bromosalicylaldehyde (2.0 g = 10 mmol), allyl bromide (2.17 ml = 25 mmol) and benzyl tributylammonium chloride (0.3 g) are dissolved in dichloromethane (50 ml). 5 ml of this solution are filled into a syringe as a supply. A second syringe is filled with a dilute sodium hydroxide solution made from 0.65 g NaOH and 50 ml water. These two syringes are each connected to a suitable pump (Harvard Apparatus pump 22) and connected to a miniaturized static silicon mixer, which in turn is connected to an indwelling element in the form of a miniaturized flow reactor, which is located on a silicon chip. This continuous reactor consists of a capillary of 100 cm in length and has a holding volume of 80 μl of liquid. A piezo crystal is attached to the chip as an ultrasonic generator, the frequency of which can be set in the range from 750 to 16,000 Hz. The present miniaturized system was first calibrated with regard to the dwell time as a function of the pump power.

The course of the reaction under various settings of frequencies and residence time was recorded using a Merck Hitachi LaChrom HPLC device. A Merck SpeedProd RP 18e with a generic gradient was used as the column. A mixture of acetonitrile and water, which contained 1% trifluoroacetic acid, was used as the solvent at a flow rate of 1.5 ml / min. The detector was set to a wavelength of 220nm. The first experiments were carried out at room temperature with a flow rate of 40 μl / min, which corresponds to a residence time of one minute. In Fig. 3 yields are shown, which were achieved under these conditions with a changed frequency. These results show that a maximum occurs at a certain frequency.

4 shows the dependence of the yield on the residence time. The tests showed that a dwell time longer than 4 minutes no longer leads to an increase in yield.

Claims

1. Microreaction channel system, characterized in that an optionally temperature-controlled micromixer is connected to a dwell element, which in turn is connected directly to a piezo element.

2. A process for carrying out phase transfer catalytic reactions, characterized in that two immiscible phases are continuously mixed intensively in a micromixer, connected to a residence element which is connected directly to a piezo element, and the reactants contained in the phases are reacted ,

3. The method according to claim 2, characterized in that the residence element is a miniaturized flow reactor.

4. The method according to claim 2, characterized in that a dwell element is used, on which the piezo element is glued.

5. The method according to claims 2 to 3, characterized in that an energy input by the piezo element with a frequency of 750 to 16,000 Hz takes place in the reaction medium.

6. The method according to claims 2 to 4, characterized in that an optimal dwell time is set as a function of the reaction speed at an optimally set excitation frequency of the piezo element.

7. The method according to claims 2 to 5, characterized in that one of the phases is an aqueous phase.