CN113149817A

CN113149817A - Method for synthesizing beta-bromohydrin by anisotropic emulsion microreactor

Info

Publication number: CN113149817A
Application number: CN202110422789.XA
Authority: CN
Inventors: 葛玲玲; 徐德华; 梁石悦; 蔡金鹏; 王海松; 郭荣
Original assignee: Yangzhou University
Current assignee: Yangzhou University
Priority date: 2021-04-16
Filing date: 2021-04-16
Publication date: 2021-07-23
Anticipated expiration: 2041-04-16
Also published as: CN113149817B

Abstract

The invention discloses a method for synthesizing β-bromo alcohol in an anisotropic emulsion microreactor. Using anisotropic emulsion droplets as microreactors, the reaction raw materials, namely olefins and N-bromosuccinimide (NBS), were selectively dissolved in the immiscible n-heptane phase and the surfactant aqueous phase, respectively. ), and selected fluorocarbon oil as the third phase, and prepared an anisotropic emulsion with fluorocarbon oil/n-heptane as the inner phase and the surfactant aqueous solution as the outer phase by the method of one-step vortex oscillation; using the anisotropic emulsion The selective solubilization and isolation of the two reaction raw materials by the multi-phase micro-region of the droplet, while giving full play to the characteristics of the anisotropic droplet multi-phase interface and multi-micro structure, realizes β-bromo without continuous stirring Static controllable synthesis of alcohols. The invention has the advantages of simple operation, low energy consumption, controllable reaction rate and easy recovery of products.

Description

Method for synthesizing beta-bromohydrin by anisotropic emulsion microreactor

Technical Field

The invention relates to the field of chemistry, in particular to a method for synthesizing beta-bromohydrin by an anisotropic emulsion microreactor.

Background

Bromohydrin is an important organic synthon in the synthesis of pharmaceuticals. Bromohydrin is used for synthesizing various intermediates widely used in drug synthesis, such as amino alcohol, hydroxy acid and the like, so that the development of a high-efficiency bromohydrin synthesis method is one of the hot research fields in the academic and industrial fields at present. Among the numerous bromohydrin synthesis methods, the bromohydroxylation reaction of olefins is the most direct method for the synthesis of bromohydrin (Sels B, et al. Nature.400, (1999), 855-. The existing bromohydrin synthesis methods are still limited by the need to use equivalent amounts of metal reagents such as AgNO₃，HgO，ZnCl₂And CuO or the like to activate the addition reaction. These activating reagents are highly toxic and relatively expensive, and are not conducive to large-scale synthesis of bromohydrin. For example, patent publication No. CN104692987A discloses a method for synthesizing bromohydrin, which uses noble metal as a catalyst. Chemists have therefore developed relatively active and stable brominating reagents such as N-bromosuccinimide (NBS) for successful use in bromohydrin synthesis (Yadav J S, et al. tetrahedron letters.46, (2005), 3569-3572). However, NBS is soluble in water but poorly soluble in most organic solvents, whereas olefinic substances are mostly poorly soluble in water but readily soluble in organic solvents. This places the two reactants in heterogeneous contact, which allows the reaction to occur only at the phase interface, greatly limiting the rate and yield of the reaction.

Emulsions are thermodynamically unstable polydispersions, with emulsion droplets ranging in size from 100 nanometers to 100 micrometers. Compared with a water-organic two-phase system, the water-organic interface area in the emulsion system is improved by millions of times. In addition, the emulsion has relatively independent micro-areas, so that related reaction substances can be limited in the micro-chamber of the liquid drop and can be prevented from contacting with other substances. It can control the diffusion of substances through the interface confinement effect, thereby regulating the reaction rate. The existing emulsion reaction system is limited in the field of material synthesis. For example, the invention patent with publication number CN102432064A discloses a method for synthesizing nano titanium dioxide, and the invention patent with publication number CN104909376A discloses a method for synthesizing nano white carbon black microspheres.

Each direction of the lightBy anisotropic emulsion is meant that the internal phase of the emulsion is composed of a plurality of immiscible liquids, including (O)₁+O₂) type/W Janus emulsion, (O)₁+O₂+O₃) Cerberus emulsion type/W. Compared to conventional emulsions, anisotropic emulsions have the following advantages: (1) the anisotropic emulsion system consists of three or more than three multiphase systems, and droplets with independent micro-areas are formed under the action of an emulsifier. The micro-area in the liquid drop and the continuous phase outside the liquid drop provide unique limited space for solubilization, isolation and slow release of various reactants, thereby providing more dimensionality for the regulation and control of the bromohydrin preparation reaction; (2) having multiple phase interfaces, e.g. O, in the droplets of the anisotropic emulsion₁interface,/W, O₂The interface of the/W and O₁/O₂And (6) an interface. By adjusting the interface area among the interfaces, the rate of the interface reaction on the interface can be effectively controlled; (3) emulsion breaking and convenient separation of the reaction system. According to the different solubilities of the products and the byproducts in different phase regions after emulsion breaking, the rapid enrichment, separation and recovery are realized by a simple liquid separation method.

Disclosure of Invention

The invention aims to provide a method for synthesizing beta-bromohydrin by using an anisotropic emulsion microreactor, which comprises the following specific steps:

1) adding different surfactants into the aqueous solution to form a surfactant aqueous solution as an external phase of the emulsion, and dissolving N-bromosuccinimide (NBS) in the surfactant aqueous solution;

2) selectively dissolving the olefin in the n-heptane phase;

3) mixing the normal heptane phase dissolved with olefin and fluorocarbon oil phase, and heating to form uniform oil phase as the inner phase of the emulsion;

4) emulsifying the water phase and the oil phase at high temperature for 3min by a one-step vortex oscillator, cooling to 25 deg.C, and standing for 24 h.

The invention takes FC-770/alkane phase as internal phase, surfactant Tween80 and FS-30 compound aqueous solution with different volume ratio as external phase, and the anisotropic emulsion is prepared by oscillation and mixing. Selectively dissolving stilbene and N-bromosuccinimide (NBS) in the inner phase and the outer phase. The invention can prepare the anisotropic emulsion on a large scale at one time and can realize the output of preparing 50L of emulsion by shaking for 3 min. The stilbene addition reaction is carried out at a droplet interface, and the control of the conversion rate of 15% to 35% in the 1 h can be realized by controlling the reaction rate through regulating and controlling the droplet topological structure. The addition reaction according to the present invention can occur at the interface of the droplets due to the difference in partition coefficients between the internal and external phases of stilbene and NBS.

The invention regulates and controls the change of the volume ratio of FC-770/n-heptane micro-regions in the anisotropic emulsion droplets from 4:1 to 1:4 by changing the volume ratio of FC-770/n-heptane of the initial oil phase.

The invention changes the kind of the surfactant and regulates the topological structure of the anisotropic emulsion liquid drop. The topology of the emulsion droplets is changed from F/H/W to H/F/W with the decrease of the TW 80 content and the increase of the FS-30 content in the system, wherein FC-770(F), n-heptane (H).

The invention changes the temperature and regulates the topological structure of the anisotropic emulsion liquid drop. The emulsion is anisotropic when the temperature is between 25 ℃ and 43 ℃, and the anisotropy of the emulsion disappears when the temperature exceeds 43 ℃ and FC-770/n-heptane dissolves as a phase.

According to the invention, through comparison of a static water-organic two-phase reaction and an emulsion reaction system, the reaction of reactants is not reacted in the static water-organic two-phase system but can occur in the emulsion system, and the result is represented by nuclear magnetism.

The invention realizes the emulsion breaking of the emulsion and the enrichment and recovery of the product and the excessive NBS in an alkane phase and a water phase by adding 0.3 times of acetonitrile by volume. The recovery of enriched product in the alkane phase was found to be as high as 83% and the recovery of NBS in the aqueous phase was found to be as high as 100%.

Drawings

FIG. 1 is a process flow diagram.

FIG. 2 is a schematic view of a reaction system.

FIG. 3 is the effect of FC-770/n-heptane volume ratios on the emulsion, with the volume ratios being a-4:1, respectively; b-2: 1; c-1: 1; d-1: 2; photomicrographs of e-1: 4.

FIG. 4 is a photomicrograph of the effect of temperature on the type of anisotropic emulsion microreactor droplets.

FIG. 5 is a fluorescent microscope photograph of the effect of surfactant species on anisotropic emulsion microreactor topology, a-2 wt% Tween80, b-1 wt% Tween80 +0.31 wt% FS-30, c-0.6 wt% Tween80 +0.43 wt% FS-30, d-0.62 wt% FS-30.

FIG. 6 is the NMR spectrum of the product in different reaction systems.

FIG. 7 is a graph showing reaction rates in different reaction systems.

FIG. 8 is a pie chart of the partition ratios of the demulsified product and excess NBS between FC-770(F), alkane phase (H), and water phase (W).

Detailed Description

Terms used in the present invention have generally meanings as commonly understood by one of ordinary skill in the art, unless otherwise specified. The following describes the present invention in further detail with reference to specific embodiments.

Example 1 below is the effect of the FC-770/n-heptane volume ratio on emulsion microreactor droplet type.

Example 1:

changing the volume ratio of FC-770/n-heptane to 1:1 for oil-water volume ratio, wherein the volume ratio is a-4: 1; b-2: 1; c-1: 1; d-1: 2; e-1: 4. Shaking for 3min under the condition to prepare emulsion.

And (3) verification: from FIG. 3 it can be seen that the FC-770/n-heptane volume ratio is 4: 1; 2: 1; 1: 1; 1: 2; the emulsion can be formed under the condition of 1:4, but the emulsion formed under the condition of 4:1 volume ratio is a single-sided emulsion, and all other volume ratios are anisotropic emulsions. The FC-770 domain volume in the droplet gradually decreases as the FC-770 domain volume in the initial oil phase decreases and the n-heptane phase increases in volume, likewise gradually increasing the n-heptane domain volume. Variations from 4:1 to 1:4 in the volume ratio of FC-770/n-heptane domains can be achieved.

Example 2 below is the effect of temperature on the type of anisotropic emulsion microreactor droplets.

Example 2

Retention of 2 wt% Tween80_(aq): n-heptane: FC-770 volume ratio was 2:1: 1. Shaking for 3min under the condition to prepare emulsion. At different temperaturesAnd taking a liquid drop micrograph at an online temperature control state. Sudan I dye is selectively dissolved in the n-heptane phase.

And (3) verification: it can be seen from fig. 4 that the temperature has an influence on the type of the droplets, and as the kind of the droplets changes from an anisotropic emulsion to a single-sided emulsion when the temperature is increased to 45 ℃, the anisotropy of the emulsion disappears.

Example 3 below is the effect of surfactant species on the anisotropic emulsion microreactor topology.

Example 3:

the volume ratio of water phase to n-heptane to FC-770 was maintained at 2:1: 1. Wherein the surfactant aqueous solution is a-2 wt% Tween80, b-1 wt% Tween80 +0.31 wt% FS-30, c-0.6 wt% Tween80 +0.43 wt% FS-30 and d-0.62 wt% FS-30 respectively. The fluorescent dye is selectively dissolved in the n-heptane phase. Shaking for 3min under the condition to prepare emulsion.

And (3) verification: from FIG. 5, it can be seen that the surfactant type can have an effect on the topology of the emulsion, which shifts from F/H/W to H/F/W with the decrease of Tween80 and the increase of FS-30 in the water phase.

Example 4 below is a nuclear magnetic map of the reaction results of different reaction systems.

Example 4:

2 parts of 0.45g of stilbene are dissolved in 30ml of n-heptane and 30ml of FC-770 mixed solution system respectively, and the mixture is heated to 50 ℃ to form a uniform oil phase. 60ml of pure water and 60ml of 2 wt% Tween80 were taken_(aq)And heated to 50 ℃. Adding the previous 2 parts of oil phase into pure water, 2 wt% Tween80_(aq)Mixing at 50 ℃, vortexing and shaking for 3min, standing at 25 ℃ for 24h, and keeping static reaction. Respectively obtaining a three-phase standing system and an F/H/W emulsion standing system. After 24h of reaction, the organic phase in the system was spin dried, extracted three times with dichloromethane and washed three times with saturated NaCl. Separating by column chromatography to obtain the final product. The material was characterized by nuclear magnetic hydrogen spectroscopy.

And (3) verification: FIG. 6 shows that the product obtained after the F/H/W emulsion standing system reacts for 24 hours is 2-bromo-1, 2-diphenylethane-1-ol, and the reaction does not occur after the two-phase standing system reacts for 24 hours.

Example 5 below is a plot of reactant conversion versus time for different systems.

Example 5:

in parallel, 0.045g of stilbene is taken and dissolved in a-3ml of n-heptane +3ml of FC-770, b-3ml of n-heptane +3ml of FC-770 solution system and c-6ml of n-heptane, respectively. Heating to 50 deg.C to obtain uniform oil phase. Respectively taking a' -6ml of 2 wt% Tween80_(aq)，b’-6ml0.625 wt％FS-30_(aq)，c’-6ml2 wt％Tween80_(aq)Heating to 50 ℃. Adding the three oil phases into a ', b ' and c ' in parallel, mixing at 50 deg.C, vortex shaking for 3min, and standing at 25 deg.C. Sampling every 1 hour, and detecting by high performance liquid chromatography.

And (3) verification: FIG. 7 shows that the reaction rates are different for different systems. Wherein a-FC-770/n-heptane/2 wt% TW 80_(aq)The reaction of the system is fastest, and b-FC-770/n-heptane/0.625 wt% FS-30_(aq)The system is reacted once, c-n-heptane/2 wt% TW 80_(aq)The system reacts slowest. This is due to differences in the topology of the emulsion.

Example 6 below is a pie chart of the distribution of the broken products of the emulsion reaction system and excess NBS between the three phases F/H/W.

Example 6:

to the fully reacted FC-770/n-heptane/surfactant in water was added 0.3 volumes of acetonitrile. The standing is divided into an upper layer (H), a middle layer (W) and a lower layer (F). Taking each layer of sample injection liquid chromatogram respectively, and taking the ratio of the obtained peak areas as a distribution ratio histogram.

And (3) verification: FIG. 8 shows that by this demulsification method, the recovery rate of the product in the paraffin phase is up to 83%, and the recovery rate of NBS in the water phase is up to 100%.

Claims

1. A method for synthesizing β-bromo-alcohol in an anisotropic emulsion microreactor, using fluorocarbon oil/linear alkane as an internal phase to prepare an anisotropic emulsion microreactor of double oil in water, and statically controllable synthesizing β -bromo alcohol, is characterized in that comprising the following steps:

1) two kinds of surfactants are added to the aqueous solution to form a surfactant aqueous solution, and a kind of raw material N-bromosuccinimide (NBS) is dissolved therein to obtain an aqueous phase containing a kind of reaction raw material (denoted as is W);

2) selectively dissolving another raw olefin in straight-chain alkane to obtain an oil phase (denoted as O1);

3) mixing the O of step 2) with the second oil phase fluorocarbon oil (denoted as O ), and heating until it becomes a homogeneous oil phase;

4) The oil phase of step 3) is used as the inner phase, and the water phase of step 1) is emulsified by one-step vortex shaker under high temperature conditions, and then lowered to room temperature, and the homogeneous oil phase is automatically separated into two phases of O1+O2, and The (O1+O2)/W type anisotropic emulsion microreactor was prepared by dispersing in the W phase in the form of two hemispherical droplets;

5) after standing the reaction system at room temperature, the reaction product β-bromo alcohol is obtained;

6) Add acetonitrile to induce emulsion breaking to form three phases, and directly separate the upper, middle and lower phases to realize the separation of products and excess raw materials.

2. The method according to claim 1, wherein the surface activity described in the step 1) is composed of non-ionic surface activity and fluorine-containing surfactant, including polyoxyethylene sorbitan monooleate series (Tween), fluorine-containing polyoxyethylene ether series (Capstone).

3 . The method according to claim 1 , wherein the dissolving methods described in the steps 1) and 2) include heating dissolving, shaking dissolving and ultrasonic dissolving. 4 .

4 . The method according to claim 1 , wherein the olefins in the step 2) include linear olefins, cyclic olefins and aromatic olefins. 5 .

5 . The method according to claim 1 , wherein the fluorocarbon oil in the step 3) comprises perfluoroalkane and polyfluoroalkane; and the heating temperature is between 45°C and 60°C. 6 .

6 . The method according to claim 1 , wherein the high temperature condition in the step 4) is between 45oC and 60oC. 7 .

7 . The method according to claim 1 , wherein the oscillation amplitude in the step 4) is between 500 rpm and 3000 rpm. 8 .

8 . The method according to claim 1 , wherein the condition for dropping to room temperature in the step 4) is 20°C to 25°C. 9 .

9 . The method according to claim 1 , wherein the range of the standing time at room temperature in the step 5) is between 6h and 48h. 10 .

10 . The method according to claim 1 , wherein the volume of acetonitrile added in the step 6) is between 0.3 times and 0.8 times the volume of the emulsion. 11 .