WO2001023328A1

WO2001023328A1 - Method for the friedel-crafts alkylation of organic compounds

Info

Publication number: WO2001023328A1
Application number: PCT/EP2000/009154
Authority: WO
Inventors: Kai Fabian; Joeran Stoldt; Hanns Wurziger; Norbert Schwesinger
Original assignee: Merck Patent Gmbh
Priority date: 1999-09-28
Filing date: 2000-09-19
Publication date: 2001-04-05
Also published as: DE19946368A1; AU7904700A; JP2003510297A; EP1216216A1

Abstract

The invention relates to a method for the Friedel-Crafts-alkylation of organic compounds and alkylation microreactors for executing said method.

Description

METHOD FOR FRIEDEL CRAFTS ALKYLATION OF ORGANIC COMPOUNDS

The present invention relates to processes for Fhedel-Crafts alkylation of organic compounds and alkylation microreactors for carrying out these processes.

Friedel-Crafts alkylation of organic compounds is a very common process in the chemical industry, and its great importance is also reflected in numerous publications on this subject.

However, carrying out Friedel-Crafts alkylations on an industrial scale brings with it safety problems and dangers. On the one hand, highly toxic chemical substances are often used, which in themselves pose a considerable risk to humans and the environment, and on the other hand Friedel-Crafts alkylations are often very exothermic, so that there is an increased risk of explosion when these reactions are carried out on an industrial scale , Obtaining an official approval according to the BlmSchG (BGBI. I No. 71 from October 26, 1998 p. 3178) for the operation of plants for Friedel-Crafts alkylation of organic compounds on an industrial scale is therefore associated with considerable expenditure.

It was therefore an object of the present invention to provide a new process for the Friedel-Crafts alkylation of organic compounds which is simple and reproducible with increased safety for

Humans and the environment as well as with good yields. Another object was to provide an apparatus for performing this method.

This object is achieved according to the invention by providing new processes for Friedel-Crafts alkylation of organic compounds in which the organic compound in liquid or dissolved form in the presence of a catalyst in liquid or dissolved form with an alkylating reagent in liquid or dissolved form in at least one microreactor is mixed, reacted during a residence time and the alkylated organic compound is isolated from the reaction mixture. -? -

A microreactor in the sense of the invention is a reactor with a volume <100 μl in which the liquids and / or solutions are mixed intimately at least once. The volume of the microreactor is preferably <10 μl, particularly preferably <1 μl. A microreactor is preferably produced from thin, interconnected silicon structures.

The microreactor is preferably a miniaturized flow reactor, particularly preferably a static micromixer. The microreactor is very particularly preferably a static micromixer, as described in WO 96/30113, which is hereby introduced as a reference and is considered part of the disclosure.

Such a microreactor has small channels in which liquids and / or chemical compounds present in solutions are preferably mixed with one another by the kinetic energy of the flowing liquids and / or solutions.

The channels of the microreactor preferably have a diameter of 10 to 1000 μm, particularly preferably from 20 to 800 μm and very particularly preferably from 30 μm to 400 μm.

The liquids and / or solutions are preferably pumped into the microreactor in such a way that they flow through them at a flow rate of 0.1 μl / min to 10 ml / min, particularly preferably 1 μl / min to 1 ml / min.

According to the invention, the microreactor can preferably be tempered.

The residence time in the sense of the invention is the time between the mixing of the organic compounds, catalysts and alkylation reagents or their solutions and the working up of this reaction solution for the analysis or isolation of the desired product (s).

The required residence time in the processes according to the invention depends on various parameters, such as the reactivity of the organic compounds, catalysts and alkylation reagents used, the desired degree of alkylation or the temperature. It is possible for a person skilled in the art to adapt the dwell time to these parameters and thus to achieve a timely response. The residence time of the reaction solution in the microreactor, if appropriate in the microreactor and the residence zone, is preferably <3 hours, preferably <1 hour.

According to the invention, the microreactor is preferably connected via an outlet to at least one retention zone, preferably a capillary, particularly preferably a temperature-controlled capillary. The liquids and / or solutions are passed into this residence zone or capillary after they have been mixed in the microreactor in order to extend their residence time.

The reaction mixture is likewise preferably passed through two or more microreactors connected in parallel or in series. The result of this is that the residence time is extended even at an increased flow rate and the components of the alkylation reaction used are converted almost completely to the desired alkylated organic compound (s).

In a further preferred embodiment of the process according to the invention, the number and the arrangement of the channels in one or more microreactor (s) are varied in such a way that the residence zone is lengthened, so that here too, with an increased flow rate, an almost complete conversion to the desired alkylated one or more organic compounds) is achieved.

The residence time of the reaction solution in the system used, comprising at least one microreactor and optionally a residence section, can also be set by selecting the flow rate of the liquids and / or solutions used.

The processes according to the invention can be carried out in a very wide temperature range, which is essentially due to the temperature resistance of the materials used for the construction of the microreactor, possibly the residence zone, and further constituents, such as, for example, connections and seals, and the physical properties of the solutions used and / or Liquids is limited. The processes according to the invention are preferably carried out at a temperature of from -90 to +150 to ° C, particularly preferably from -20 to +100 ° C, very particularly preferably from -10 to +80 ° C. The processes according to the invention can be carried out either continuously or batchwise. They are preferably carried out continuously.

To carry out the process according to the invention for Friedel-Crafts alkylation of organic compounds, it is necessary that the alkylation reaction be carried out in a homogeneous liquid phase, since otherwise the channels present in the microreactors become blocked.

The course of the alkylation reaction in the processes according to the invention can be followed and, if necessary, regulated using the various analytical methods known to the person skilled in the art. The course of the reaction is preferably followed by chromatography, particularly preferably by gas chromatography, and, if appropriate, regulated.

The alkylated organic compounds can also be isolated by the various methods known to the person skilled in the art. The alkylated product (s) is / are preferably isolated from the reaction mixture by extraction, preferably with an organic solvent or by precipitation, preferably with an organic solvent and / or water, particularly preferably with water.

All organic compounds known to the person skilled in the art as substrates of Friedel-Crafts alkylation reactions can be used as organic compounds in the processes according to the invention.

Aromatic or heteroaromatic compounds are preferably used as organic compounds. These aromatic or heteroaromatic compounds include both monocyclic and polycyclic compounds, as well as compounds which have a monocyclic and / or polycyclic, homo- or heteroaromatic basic structure or a partial structure, e.g. in the form of substituents.

Particularly preferred aromatic compounds are benzene, naphthalene, azulene, anthracene, phenanthrene, pyrene, fluorene, quinones such as ortho and para-benzoquinone, naphthoquinones, flouronones, anthrones, phenanthrones, anthraquinones and / or their derivatives, in particular their alkyl, derivatives used. Particularly preferred heteroaromatic compounds are oxygen-containing, heteroaromatic compounds and / or their derivatives, very particularly preferably furans, such as, for example, benzanellated furans, dibenzofurans, dibenzodioxanes, pyrylium cations and benzopyranones. Also particularly preferred are nitrogen-containing, heteroaromatic compounds and / or their derivatives, such as, for example, pyrroles, pyrazoles, imidazoles, triazoles, tetrazoles, pyridines, pyrazines, pyrimidines, pyridinium salts, triazines, tetrazines, pyridine-N-oxides, benzanellated pyrroles , such as indoles, carbazoles, benzimizazoles or benzotriazoles, phenanzine, quinolines, isoquinolines, cinnolines, quinazolines, quinoxalines, phenanthroline, bipyridyls and their higher homologues, acridines, acridones, and / or pyrene. Sulfur-containing, heteroaromatic compounds and / or their derivatives, such as, for example, thiophenes, benzanellated thipophenes, in particular benzothiophenes or dibenzothiophenes, and also acenaphthylenes, thiazoles, isothiazoles, biphenylenes, purines, benzothiadiazoles, oxazoles and / or

Isoaxazole.

Also preferred as organic compounds are organometallic compounds whose organic partial structure can be alkylated by a Friedel-Crafts alkylation. Particularly preferred organometallic compounds are metallocenes of metals in the fourth to eighth subgroup of the periodic table, very particularly preferably metallocenes of metals in the fourth to eighth subgroup of the periodic table with at least one cyclopentadienyl ligand in the processes according to the invention.

All alkylation reagents known to the person skilled in the art can be used as alkylation reagents in the processes according to the invention. Preferred alkylation reagents are olefins, particularly preferably ethene, propene, dodecene or linear olefins with a chain length of 20 to 30 carbon atoms, alkyl halides, particularly preferably methyl chloride, methyl iodide, ethyl chloride, isopropyl chloride, tert-butyl chloride, benzyl chloride or cyclohexyl chloride, alcohols, ethers, esters inorganic and organic acids, epoxides, aldehydes, ketones, thiols, dialkyl sulfates, alkyl p-tolyl sulfonates, trifluoromethanesulfonic acid or their esters, aliphatic diazo compounds and / or trialkyloxonium tetrafluoroborates. It is essential for the processes according to the invention that the organic compounds, alkylation reagents and catalysts used are either themselves liquid or are in dissolved form. If these compounds are not themselves already in liquid form, they must therefore be used in a suitable one before carrying out the processes according to the invention

Solvent are dissolved. Preferred solvents are halogenated hydrocarbons, particularly preferably dichloromethane, chloroform, 1, 2-dichloroethane or 1, 1, 2,2-tetrachloroethane, paraffins, particularly preferably hexane or ligroin, ether, particularly preferably diethyl ether, acid amides, particularly preferably N, N-dimethylformamide, nitriles, particularly preferably acetonitrile, carbon disulfide, nitroaliphatics, particularly preferably nitromethane, nitroaromatics, particularly preferably nitrobenzene or mixtures thereof.

Ionic liquids which are liquid eutectics at room temperature are also preferably used as solvents. Particularly preferred ionic liquids are N-butyl-N-methylimidazolium tetrachloroaluminate, N-ethyl-N-methylimidazolium tetrachloroaluminate, N-ethyl-N-methylimidazolium tetrafluoroborate, N-alkylated pyridinium imidazolium salts, in particular their tetrafluoro or hexafluorobluoro or hexafluorobluorobluorobluoroborate or their tetrafluoro or hexafluoroborate or hexafluoroborate or especially their tetrafluoro or hexafluoroborate or hexafluorobluorobluorobluoride or especially their tetrafluoro or hexafluoroborate or their tetrafluoro or hexafluoroborate - rophosphates or mixtures thereof.

The molar ratio of organic compound to alkylation reagent used in the processes according to the invention depends on the one hand on the reactivity of the organic compounds, catalysts and alkylation reagents used and on the other hand on the desired degree of alkylation. The degree of alkylation itself depends on a number of other parameters, such as the concentration of the reagents used, e.g. Temperature, type of catalyst or residence time. It is possible for the person skilled in the art to adapt the various parameters to the respective alkylation reaction in such a way that the desired single or multiple alkylated product is obtained.

The molar ratio of organic compound to alkylating reagent is preferably 1 to 10, preferably 1, 1 to 2 and particularly preferably 1, 2 to 1, 5 for the preparation of a mono-alkylated compound. All catalysts known to the person skilled in the art and suitable for Friedel-Crafts alkylations can be used as catalysts in the processes according to the invention.

Lewis acids are preferably also used as catalysts, if appropriate also dissolved in ionic liquids, protonic acids, ionic liquids, organometallic catalysts and / or mixtures thereof.

Particularly preferred catalysts chloroacetic acid, trifluoroacetic sigsäureanhydrid, trifluoromethanesulfonic anhydride, dihalogenated phosphoric, sulfuric, hydrochloric, phosphoric, sulfonic acids, very particularly preferably alkyl sulfonic acids such as methanesulfonic acid or arylsulfonic acid, iron trihalides, tin tetrachloride, aluminum halides, alkylaluminum halides, boron trihalides, ionic liquids, which at Eutectics which are liquid at room temperature, such as, for example, N-butyl-N-methylimidazolium tetrachloroaluminate, N-ethyl-N-methylimidazolium tetrachloroaluminate, N-ethyl-N-methylimidazolium tetrafluoroborate or N-alkylated pyridinium imidazolium salts or, in particular, their tetrafluoroborates Hexafluorophosphate, antimony halides, BeCI ₂ , CdCI ₂ , ZnCI ₂ , GaCI ₃ , BiCI _3. TiCU, ZrCI ₄ , VCI, metal alkyls, metal alkoxides, TiCI ₂ (CH ₃ ) ₂ , Pd (PPh ₃ ), RuCI ₂ (PPh ₃ ) ₂ or mixtures of these catalysts used.

The amount of the catalyst used in the process according to the invention is preferably between 0.1 and 110 mol%, particularly preferably between 1 and 100 mol%, based on the amount of organic compound used.

Another object of the invention is an alkylation microreactor for carrying out the process according to the invention. This alkylation micro-reactor has at least one mixing element and optionally a residence zone and its volume, without the volume of the residence zone, is preferably <10 μl, particularly preferably <1 μl.

In a preferred embodiment, the alkylation microreactor is a static micromixer. In a further preferred embodiment of the alkylation microreactor, it has a residence zone which is a capillary which is connected to an outlet of the alkylation microreactor. The capillary is preferably a temperature-controllable capillary.

The alkylation microreactor itself can likewise preferably be temperature-controlled.

In the methods according to the invention, the risk to humans and the environment from chemicals being released is considerably reduced. Furthermore, the risk of explosion in the case of very strongly exothermic alkylation reactions is reduced, inter alia, by an improved mass and heat transport compared to conventional systems. An official approval according to the BlmschG (BGBI. I No. 71 of October 26, 1998 p. 3178) for the operation of systems for the implementation of the method according to the invention is therefore much easier to obtain. It is also particularly advantageous that the processes according to the invention can be carried out continuously. As a result, they can be carried out more quickly and more cost-effectively than conventional methods, and it is possible to produce any amounts of the alkylated organic compounds without great expenditure on measurement and control. The course of the alkylation reaction can be regulated very quickly in the process according to the invention. The alkylation of organic compounds by the processes according to the invention also enables better control over the reaction time and reaction temperature than is possible in the conventional processes. By implementing short reaction times, the proportion of mono-alkali products can be increased compared to double and triple-alkali products. The temperature can be individually selected and kept constant in each volume element of the system. The alkylated organic products can thus be obtained in very good and reproducible yields.

The invention is explained below using an example. This example only serves to explain the invention and does not restrict the general idea of the invention.

example

Friedel-Crafts alkylation of benzene with Cvclohexen:

(1) (2) (3)

The Friedel-Crafts alkylation of benzene (1) with cyclohexene (2) was carried out in a static micromixer with 11 integrated mixing stages (Ilmenau University of Technology, Faculty of Mechanical Engineering, Dr.-Ing. Norbert Schwesinger, Postfach 100565, D-98684, Ilmenau) Each individual mixing stage had a size of 0.8 mm x 0.8 mm x 0.6 mm and a volume of 0.125 μl.

The total pressure loss across all 11 mixing stages was approx. 1000 Pa. The static micromixer was connected via an outlet and an Omnifit medium pressure HPLC connector component (Omnifit, Great Britain) to a Teflon capillary with an inner diameter of 0.25 mm and a length of 0.9 m. The static micromixer and the Teflon capillary were tempered in a double-jacket vessel filled with ethanol and thermostated at 0 ° C.

A 20 ml polypropylene syringe was filled with a mixture of 4 ml (0.045 mol) benzene and 5 ml cyclohexene and a 1 ml glass syringe with a metal tip was filled with 1 ml (0.019 mol) 96% sulfuric acid. The contents of both syringes were then transferred to the static micromixer using a metering pump (Harvard Apparatus Inc., Pump 22, South Natick, Massachussets, USA). The flow rate was set at 10 ul / min.

To determine the yield of the alkylated reaction products, the mixed reaction solution was stirred into a beaker with 50 ml of water. The system of static micromixer and Teflon capillary was then rinsed first with 10 ml of water and then with 10 ml of dichloromethane. The combined liquid phases were then extracted three times with 20 ml dichloromethane each time. The combined organic extracts were dried over magnesium sulfate and the solvent was removed in vacuo. 8.3 g (corresponding to 58% of the theoretical yield) of a colorless oil were obtained, which crystallized out at a temperature of −20 ° C. in the form of white crystals. The content of simply alkylated product (3) was 50 by a combined GC-MS analysis Area% of the chromatogram determined. In addition, 20 area% of cyclohexene and 5 area% of double-alkylated products were detected.

Claims

PATENT CLAIMS

1. A method for Friedel-Crafts alkylation of organic compounds, characterized in that the organic compound is mixed in liquid or dissolved form in the presence of a catalyst in liquid or dissolved form, with an alkylating reagent in liquid or dissolved form in at least one microreactor, while a residence time and the alkylated organic compound is isolated from the reaction mixture.

2. The method according to claim 1, characterized in that the microreactor is a miniaturized flow reactor.

3. The method according to claim 1 or 2, characterized in that the microreactor is a static micromixer.

4. The method according to any one of claims 1 to 3, characterized in that the microreactor is connected via an outlet to a capillary, preferably a temperature-controlled capillary.

5. The method according to any one of claims 1 to 4, characterized in that the volume of the microreactor is <10 ul, preferably <1 ul.

6. The method according to any one of claims 1 to 5, characterized in that the microreactor can be tempered.

7. The method according to any one of claims 1 to 6, characterized in that the microreactor has channels with a diameter of 10 to 1000 microns, preferably 20 to 800 microns, particularly preferably 30 microns to 400 microns.

8. The method according to any one of claims 1 to 7, characterized in that the reaction mixture flows through the microreactor at a flow rate of 0.1 ul / min to 10 ml / min, preferably 1 ul / min to 1 ml / min.

9. The method according to any one of claims 1 to 8, characterized in that the residence time of the compounds used in the microreactor, optionally in the microreactor and the capillaries is <3 hours, preferably <1 hour.

10. The method according to any one of claims 1 to 9, characterized in that it is carried out at a temperature of -90 to +150 to ° C, preferably -20 to +100 ° C, particularly preferably from -10 to +80 ° C ,

11. The method according to any one of claims 1 to 10, characterized in that the course of the reaction is followed chromatographically, preferably gas-chromatographically and optionally regulated. 0

12. The method according to any one of claims 1 to 11, characterized in that the alkylated product is isolated from the reaction mixture by extraction or precipitation.

_j 5

13. The method according to any one of claims 1 to 12, characterized in that as alkylating reagents olefins, alkyl halides, alcohols, ethers, esters of inorganic or organic acids, epoxides, aldehydes, ketones, thiols, dialkyl sulfates, alkyl-p-tolyl sulfonates, trifluoromethanesulfonic acid - re or their esters, aliphatic diazo compounds and / or trialky

20 loxonium tetrafluoroborates can be used.

14. The method according to any one of claims 1 to 13, characterized in that the molar ratio of organic compound to alkylating reagent 1 to 10, preferably 1, 1 to 2 and particularly preferably 1, 2 to 1, 5 for the preparation of a simple alkylated compound.

25

15. The method according to any one of claims 1 to 14, characterized in that Lewis acids, optionally also dissolved in ionic liquids, protonic acids, ionic liquids, organometallic catalysts and / or mixtures thereof are used as the catalyst.

30

16. The method according to any one of claims 1 to 15, characterized in that between 0.1 and 110 mol%, preferably between 1 and 100 mol% of the catalyst, based on the amount of organic compound used, are used.

_

17. alkylation microreactor comprising at least one mixing element and optionally a residence zone, characterized in that the Volume of the alkylation microreactor, without the volume of the residence zone, is <10 μl, preferably <1 μl.