CN102060654B - Method for selective chlorination of alkyl side chains on benzene ring - Google Patents
Method for selective chlorination of alkyl side chains on benzene ring Download PDFInfo
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Abstract
The invention relates to a method for selective chlorination of alkyl side chains on a benzene ring, which comprises the steps of: reacting a-H-containing alkyl arene as a raw material and a reactant of hydrogen peroxide with volume content of 30% and hydrochloric acid with volume content of 36-38%, as a chlorinating agent, for 1-2 hours in a water bath at 50-70 DEG C in the presence of a glacial acetic acid, separating the liquid to obtain a chlorinated alkyl benzene mixture; and carrying out elective chlorination on alkylbenzene by changing the reaction temperature and content of the hydrogen peroxide to obtain halides on the side chains of the benzene ring. The halides on the side chains of the benzene ring, prepared with the method disclosed by the invention, can be used in the fields of chemical raw materials, medicinal intermediates, medical disinfectants and the like. Compared with a conventional method for the side-chain chlorination of the alkylbenzene, the method has the advantages of cheap and easily-obtained raw materials, relatively smaller erosion on equipment, mild reaction condition, high selectivity and short time and is a safe and reliable synthetic method with high efficiency and low cost.
Description
Technical field
The present invention relates to the selective chlorination of alkyl group side chain α-H on a kind of phenyl ring, belong to the preparation method of Minute Organic Synthesis, the halogenide on the benzene ring side chain of the present invention's preparation can be used as industrial chemicals, pharmaceutical intermediate, the fields such as agricultural insecticide.
Background technology
On phenyl ring, the chlorination of alkyl group side chain α-H is the important initial step of the many important industrial chemicals of preparation, medicine intermediate.But what in industry, the chlorination of alkyl-alpha-H on relevant aromatic ring side chain is mainly adopted at present is under illumination condition, with chlorine to benzene and side chain chlorination thereof.There are many drawbacks in the method for this halogenation based on the free radical principle, and wherein the most outstanding is exactly etching problem and environmental protection problem in production process.For example, the type reaction feature of free radical halogenation is exactly to use chlorine and pyroreaction.Whole chlorination production process is quite serious to the corrosion of equipment, and wherein main corrosive medium is HCl, HC1O and wet chlorine.Therefore the conversion unit of whole chloridization process process, slightly heat up in a steamer with rectifying device etc., major part all must be taked anti-corrosion measure.However, slightly heat up in a steamer with distillation operation in, produce corrosion when material enters condensation, can only use 3 months at most with the condenser of plain carbon stool manufacturing, and need to adopt graphite condenser etc.Adopt glass equipment and pipeline, although greatly improved the corrosion resistance nature of equipment, its heatproof sudden turn of events is relatively poor, and fragility is larger, can bring very big hidden danger to production equally.
And, with chlorine as the initial action raw material, not only need to use specific device and loop to improve the utilization ratio of chlorine, this reaction also must be carried out under illumination and hot conditions, the chlorine radical of the high reaction activity that produces of reaction is when substituted alkyl carries out chlorination on to benzene, also can produce a chloro and get mix products to many chloros, reaction preference is not only low, and the desired high temperature of reaction mechanism has more aggravated the corrosion of reaction medium to equipment.As potential potential safety hazard, using and revealing of chlorine is also a problem that can not be ignored.
In order to overcome the problems referred to above, seek suitable chlorination reagent most important.At present lower to the method selectivity of carrying out halogenation of benzene ring side chain with radical reaction mechanism, this be the chlorine radical activity that produces due to illumination strong due to.For example, the photochemical chlorination of toluene is mainly for the production of benzyl chloride, xylylene dichlorides and phenyl-chloroform.But except the methyl energy chlorination of toluene molecule, also can form unwanted a small amount of chlorinated derivatives on aromatic ring.This is because the chlorine radical reaction is very active, so chlorination generally can obtain the compound that various side reaction things coexist.This makes the halogenation selectivity of benzene ring side chain often relatively poor, the industrial process that often can only rely on weighting method judgement reaction.In addition, along with the increase of mixture chlorination degree, the ratio of the chlorinated derivatives on aromatic ring also can significantly increase.Some industrialization adopt take in application incomplete chlorination with the restriction derivative formation, but this relative increase cost value.Excessive chlorination not only can generate more by product, makes to specify the halogenated intermediates once through yield lower, and the fractionation from mixed liquid of relevant halohydrocarbon, or the recrystallization separation loss is also larger, causes chlorine or alkylbenzene utilization ratio in raw material to reduce.Some documents improve synthetic route, but most appointing based on the free radical reaction pattern, thereby fundamentally can't change the status quo.
Summary of the invention
Technical problem to be solved by this invention is: for the deficiencies in the prior art, provide that a kind of cost is low, low temperature, highly selective, operation is simple and easy, and need not too much to change the selective chlorination of alkyl group side chain on the phenyl ring of existing equipment.
The present invention solves its technical problem and adopts following technical scheme:
The selective chlorination of alkyl group side chain on phenyl ring provided by the invention, the α-H selective chlorination of alkyl group side chain on a kind of phenyl ring, the method is: adopting the alkyl aromatics that contains α-H is raw material, under the Glacial acetic acid environment, take content as 30% hydrogen peroxide and content as the 36-38% hydrochloric acid reaction as chlorizating agent, be under 50 ℃ of-70 ℃ of water-baths in temperature of reaction, reacted 1-2 hour, obtain the chloro alkylbenzene mixture after separatory; The temperature of reacting by change and the content of hydrogen peroxide can be realized the Selective chlorination of alkylbenzene.
The present invention specifically adopts the method that comprises the following steps:
(1) will contain the alkyl aromatics of α-H and Glacial acetic acid in 0.1 mole: the ratio of 40 milliliters is placed in four-hole boiling flask.Glacial acetic acid can carry out chlorination to described alkyl aromatics as solvent;
(2) mechanical stirring, and load onto thermometer and reflux condensing tube, control the water bath with thermostatic control temperature between 50～70 ℃, at the uniform velocity stir;
(3) according to monochloro generation or two chloro needs, concentrated hydrochloric acid and hydrogen peroxide are pressed the 2:1 volume ratio, first adding concentration is 40～80 milliliters of the concentrated hydrochloric acids of 36-38%, then at the uniform velocity dripping in proportion concentration is 20～40 milliliters, 30% hydrogen peroxide, after hydrogen peroxide is added dropwise to complete, continues stirring and reacted fully in 1～2 hour.The reaction of hydrogen peroxide and concentrated hydrochloric acid can provide the chlorine source, and the alkyl of benzene ring side chain is carried out chlorination;
(4) reaction is complete, collects lower floor's yellow-green liquid or chlorination solid product corresponding to direct filtration;
(5) with the mode of fractionation or the mode of underpressure distillation, the separated and collected cut obtains the halogenide on benzene ring side chain, and this halogenide is a chlorinated derivative or dichloro-derivative;
Perhaps,
(6) directly adopt frozen water cooling after, direct decompress filter separate solid, this solid is the halogenide on benzene ring side chain, this halogenide is dichloro-derivative or three chloro derivatives.
The alkyl aromatics of the described α of containing-H can adopt single substituted alkyl benzene, two substituted alkyl benzene or three substituted alkyl benzene.
Described single substituted alkyl benzene can be adopted as toluene.
Described two substituted alkyl benzene can adopt o-Xylol, m-xylene or p-Xylol.
Described three substituted alkyl benzene can adopt sym-trimethylbenzene.
A described chlorinated derivative is benzyl chloride; α, α '-dichloro-toluene; α, α ' m-xylene; α, α '-p-Xylol; α, α ', α ' '-three chloro sym-trimethylbenzene.
Described dichloro-derivative is α, alpha-single chloro toluene; α, α, α ', α '-tetrachloro is for o-Xylol; α, α, α ', α '-m-xylene; α, α, α ', α '-p-Xylol.
Described three chloro derivatives are α, α, α-three chloro toluene.
Halogenide on the benzene ring side chain of the present invention's preparation can be used as industrial chemicals, pharmaceutical intermediate or sterilizing agent.
The present invention compared with prior art has advantages of following main:
The chlorination mode free radical chlorination different from the past that the present invention adopts, and be based on ionic reaction mechanism, so the selectivity of chlorination reaction is higher.Wherein, the chlorination reaction of many alkyl substituted benzenes is different from the chlorination of toluene, and on a plurality of alkyl methyls, single the replacement with two substitution products is solid.For example the monochloro on the o-Xylol alkyl is for product, α, and the fusing point of α '-dichloro-o-Xylol is 55 ~ 57 ℃; Two chloro-products on alkyl, α, α, α ', α '-tetrachloro is 87 ~ 89 ℃ for the fusing point of o-Xylol.Therefore during the design reaction, revise slightly on the basis of toluene chlorination optimal conditions, temperature is controlled at 60 ~ 65 ℃, can control in reaction process tetrachloro and for the generation of product, also can avoid further chloro.Under this reaction conditions, the product of generation can be separated out very soon.Trisubstitution product do not detected in last chlorizate and occur, show that the appearance of product precipitation has further improved the selectivity of chlorination reaction.And compare in this, the single chlorination yield that replaces on the toluene alkyl is relatively on the low side, and selectivity is also relatively poor.
The present invention adopts above-mentioned preparation method, adopts Glacial acetic acid as the chlorination medium, has reduced to a certain extent the corrosion of concentrated hydrochloric acid to equipment.
The present invention adopts above-mentioned preparation method, adopts mechanical stirring, controls temperature of reaction at 50 ~ 70 ℃, has avoided the corrosion of acid to equipment under high temperature in the free radical reaction, greatly reduces simultaneously the energy consumption of reaction.
The present invention adopts above-mentioned preparation method, adopts to drip hydrogen peroxide and hydrochloric acid generation chlorination reagent, makes reaction controlled, and has greatly improved the selectivity of reaction.
The present invention adopts above-mentioned preparation method, and total chlorination yield is between 58.29% ~ 84.43.
The present invention is directed to the problem that prior art exists, used conventional equipment and reagent, can under relatively mild reaction conditions, optionally realize the chlorination of alkyl-alpha-H on phenyl ring.The inventive method is simple, need not that existing equipment is carried out larger change just can realize.This chlorated liquid is important chemistry, industrial chemicals through separating the different products that obtain, and in chemical industry, medicine and other fields, good application prospect is arranged.
Embodiment
The present invention will be further described below in conjunction with embodiment, but be not limited only to following embodiment.
Embodiment 1: benzyl chloride synthetic
Add 12.0 mL (0.1mol) toluene in the four-hole bottle that is connected to reflux condensing tube, thermometer, dropping funnel and mechanical stirring head, the concentrated hydrochloric acid of 80mL and 40mL Glacial acetic acid, under slowly stirring, little fire is heated to 65oC, by slowly the drip hydrogen peroxide of 20mL of dropping funnel, control the speed that drips hydrogen peroxide, liquid in reaction flask is light yellow being advisable, and slowly drips hydrogen peroxide, controls the speed that drips hydrogen peroxide, drip rear continuation reaction 2 hr, obtain the chloro mixture.Tell organic layer with separating funnel, water 10mL chloroform extraction merges organic phase, with 20 mL saturated sodium bicarbonate solution washing 3 times, then uses 20 mL deionized water wash 3 times, and anhydrous magnesium sulfate drying spends the night successively.The chloro mixture carries out rectifying separation with fractionation plant, the calculated yield of weighing respectively.The benzyl chloride yield is 4.65g, 37.09%; α, alpha-single chloro toluene yield is 2.04g, 12.68%; α, α, α-three chloro toluene yield is 2.50g, 12.80%.Total chlorination yield 62.57% of three kinds of chloro mixtures.
Embodiment 2: α, alpha-single chloro toluene synthetic
Add 12.0 mL (0.1mol) toluene in the four-hole bottle that is connected to reflux condensing tube, thermometer, dropping funnel and mechanical stirring head, the concentrated hydrochloric acid of 80mL and 40mL Glacial acetic acid, under slowly stirring, little fire is heated to 65 oC, by slowly the drip hydrogen peroxide of 40mL of dropping funnel, control the speed that drips hydrogen peroxide, liquid in reaction flask is light yellow being advisable, and slowly drips hydrogen peroxide, controls the speed that drips hydrogen peroxide, drip rear continuation reaction 1 hr, obtain the chloro mixture.Tell organic layer with separating funnel, water 10mL chloroform extraction merges organic phase, with 20 mL saturated sodium bicarbonate solution washing 3 times, then uses 20 mL deionized water wash 3 times, and anhydrous magnesium sulfate drying spends the night successively.The chloro mixture carries out rectifying separation with fractionation plant, the calculated yield of weighing respectively.The benzyl chloride yield is 1.21g, 9.53%; α, alpha-single chloro toluene yield is 8.71g, 54.08%; α, α, α-three chloro toluene yield is 16.11%.Total chlorination yield 3.15,79.72% of three kinds of chloro mixtures.
Embodiment 3: α, α '-dichloro-o-Xylol
Add 6.0 mL (0.05mol) o-Xylol in the four-hole bottle that is connected to reflux condensing tube, thermometer, dropping funnel and mechanical stirring head, 40 mL concentrated hydrochloric acids, 40 mL Glacial acetic acid, under slowly stirring, little fire is heated to 60 ℃, slowly drip the 20mL hydrogen peroxide, control the speed that drips hydrogen peroxide, control temperature and drip rear continuation reaction 2 hr at 60 ~ 65 ℃.Fast filtering while hot after reaction finishes, standing, frozen water is cooling, the muriate that obtains.Quick suction filtration, solid washs with a small amount of frozen water, spends the night in the vacuum drying oven inner drying after draining, and obtains the 7.16g solid, productive rate 88.15%, m.p.50-53 ℃.
Embodiment 4: α, and α, α ', α '-tetrachloro is for o-Xylol
Add 6.0 mL (0.05mol) o-Xylol in the four-hole bottle that is connected to reflux condensing tube, thermometer, dropping funnel and mechanical stirring head, 40 mL concentrated hydrochloric acids, 40 mL Glacial acetic acid and phase-transfer catalysts, under slowly stirring, little fire is heated to 60 ℃, slowly drip hydrogen peroxide, control the speed that drips hydrogen peroxide, control temperature and drip rear continuation reaction 2 hr at 60 ~ 65 oC.Fast filtering while hot after reaction finishes, standing, cooling, the muriate that obtains.Suction filtration, solid washs with a small amount of frozen water, spends the night in the vacuum drying oven inner drying after draining, the 10.75g that weighs, productive rate 88.15%, m.p.84-86 ℃.In practice, product need not to be further purified the preparation o-phthalaldehyde(OPA) that just can be hydrolyzed.
Embodiment 5: α, α ', α ' '-three chloro sym-trimethylbenzene (equal three benzyl chlorides) synthetic
Add 7.0 mL (0.05mol) toluene in the four-hole bottle that is connected to reflux condensing tube, thermometer, dropping funnel and mechanical stirring head, the concentrated hydrochloric acid of 80mL and 40mL Glacial acetic acid, under slowly stirring, little fire is heated to 60oC constant temperature, by slowly the drip hydrogen peroxide of 20mL of dropping funnel, control the speed that drips hydrogen peroxide, liquid in reaction flask is light yellow being advisable, and slowly drips hydrogen peroxide, controls the speed that drips hydrogen peroxide, drip rear continuation reaction 2 hr, obtain chloro-product.Fast filtering while hot after reaction finishes, standing, cooling, the muriate that obtains.Suction filtration, solid washs with a small amount of frozen water, spends the night in the vacuum drying oven inner drying after draining, and weighs, and equal three benzyl chlorides are 8.75g, and yield is 78.82%.
Embodiment 6: the halid application on benzene ring side chain
As industrial chemicals, for example phenyl aldehyde is synthetic.
Take the α of above-mentioned preparation, alpha-single chloro toluene 10g, need not purification process, directly be placed in the clean three-necked bottle that spherical condensation tube and magnetic stirring apparatus are housed, then add 17.5g vulkacit H and 100 ml ethanol: water is the mixing solutions of 3:2, under refluxad, slowly adding massfraction is the hydrochloric acid of 37 %, react to the solution clarification that becomes, stopped reaction is removed the ethanol in solution, then steam distillation steams thick products benzene formaldehyde, use the sherwood oil recrystallization again, get the 5.60g light yellow crystal, yield is 84.8%.
Embodiment 7: the halid application on benzene ring side chain
Pharmaceutical intermediate, for example o-phthalaldehyde(OPA) is synthetic.
O-phthalaldehyde(OPA) is at the sterilizing agent, the sterilant that are medically a kind of new highly effective and safe, can be used for hospital in peep the sterilization of border surgery instrument; Pharmaceutically, it is one of raw material of synthetic platelet aggregation inhibitor indoles ripple sweet smell; The raw material that is chemically Minute Organic Synthesis is OAR, can be used as the mensuration of the alkaloidal reagent of amine and photofluorometer histamine.
take the α of above-mentioned preparation, α, α ', α '-tetrachloro is for o-Xylol 10g, need not purification process, directly be placed in the clean three-necked bottle that spherical condensation tube and magnetic stirring apparatus are housed, then add 17.5g vulkacit H and 100 ml ethanol: water is the mixing solutions of 3:2, under refluxad, slowly adding massfraction is the hydrochloric acid of 37 %, react to the solution clarification that becomes, stopped reaction, remove the ethanol in solution, then steam distillation steams thick product o-phthalaldehyde(OPA), use again the sherwood oil recrystallization, get the 4.56g light yellow crystal, yield is 85.7%.
Claims (4)
1. the selective chlorination of alkyl group side chain on a phenyl ring, it is characterized in that the α of alkyl group side chain on a kind of phenyl ring-H selective chlorination, the method is: adopting the alkyl aromatics that contains α-H is raw material, under the Glacial acetic acid environment, take volume content as 30% hydrogen peroxide and volume content as the 36-38% hydrochloric acid reaction as chlorizating agent, be under 50 ℃ of-70 ℃ of water-baths in temperature of reaction, reacted 1-2 hour, obtain the chloro alkylbenzene mixture after separatory; The temperature of reacting by change and the content of hydrogen peroxide are realized the Selective chlorination of alkylbenzene; The alkyl aromatics of the described α of containing-H is single substituted alkyl benzene, two substituted alkyl benzene or three substituted alkyl benzene; Described single substituted alkyl benzene is toluene; Described two substituted alkyl benzene are o-Xylol, m-xylene or p-Xylol; Described three substituted alkyl benzene are sym-trimethylbenzene.
2. selective chlorination according to claim 1 is characterized in that the method comprises the following steps:
(1) will contain the alkyl aromatics of α-H and Glacial acetic acid in 0.1 mole: the ratio of 40 milliliters is placed in four-hole boiling flask;
(2) mechanical stirring, and load onto thermometer and reflux condensing tube, control the water bath with thermostatic control temperature between 50～70 ℃, at the uniform velocity stir;
(3) according to monochloro generation or two chloro needs, concentrated hydrochloric acid and hydrogen peroxide are pressed the 2:1 volume ratio, first adding concentration is 40～80 milliliters of the concentrated hydrochloric acids of 36-38%, then at the uniform velocity dripping in proportion concentration is 20～40 milliliters, 30% hydrogen peroxide, after hydrogen peroxide is added dropwise to complete, continues stirring and reacted fully in 1～2 hour;
(4) reaction is complete, collects lower floor's yellow-green liquid or chlorination solid product corresponding to direct filtration;
(5) with the mode of fractionation or the mode of underpressure distillation, the separated and collected cut obtains the muriate on benzene ring side chain;
Perhaps,
(6) directly adopt frozen water cooling after, direct decompress filter separate solid, this solid is the muriate on benzene ring side chain.
3. selective chlorination according to claim 2, is characterized in that in step (5), and separated and collected cut, the muriate on the gained benzene ring side chain are a chlorinated derivative or dichloro-derivative.
4. selective chlorination according to claim 2, is characterized in that in step (6), the muriate on the gained benzene ring side chain is the dichloro-derivative.
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| CN112142552A (en) * | 2019-06-26 | 2020-12-29 | 张家港九力新材料科技有限公司 | Method for preparing p-dichlorobenzyl through ultraviolet light induced catalysis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1110270A (en) * | 1994-12-13 | 1995-10-18 | 浙江大学精细化工厂 | Method and equipment for producing benzyl fluoride |
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| IT1263960B (en) * | 1993-02-24 | 1996-09-05 | Enichem Sintesi | PROCEDURE FOR THE PHOTOCLORURATION OF ALCHYLAROMATIC COMPOUNDS |
| CN100415700C (en) * | 2006-04-14 | 2008-09-03 | 浙江巍华化工有限公司 | Method of producing chlorobenzyl by photochlorination |
| CN100532338C (en) * | 2007-06-18 | 2009-08-26 | 南京工业大学 | Process for producing benzyl chlorides chemical compound |
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