钝化芳烃氯甲基化反应研究
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摘要
Blanc氯甲基化是一种很经典的反应,是在芳香族化合物中引入氯甲基的重要方法。在农药、医药、染料和香料等精细化学品的合成中应用非常广泛。导入芳香烃的氯甲基可以再转化成其它基团,如-CH_2OH、-CHO、-CH_2CN、-CH_2NH_2、-CH_3、-CH_2R等,从而容易的制得一系列新的衍生物。
本文报道的这种方法是含有钝化基团的芳香化合物进行氯甲基化反应的新方法,即将芳香族化合物与氯磺酸和多聚甲醛反应,从而将氯甲基引入芳环。这里所说的芳香族化合物要含有至少一个含有吸电子基团的苯环和一个苯环上可被取代的氢。在经典的Blanc氯甲基化反应中,根据它的反应机理可得知:芳环上连有推电子基团时,有利于反应的进行;而连有强吸电子基团时,则不利于反应进行。而本文所报道的这种方法对于含硝基和三氟甲基的苯的氯甲基化反应是非常有效的,因为它们对以前报道过的氯甲基化试剂所进行直接氯甲基化反应是有阻碍作用的。通过采用这种新方法,改变了整个反应体系,无需再加入其它Lewis酸,反应选择性大为提高,副产物减少,收率明显得到提高。该反应减少了对环境的危害,实现了环境友好的氯甲基化反应。
采用这种新方法完成了2-氯-5-氯甲基苯腈、1-氯-2-氯甲基-4-三氟甲基苯、1,2-二氯-3-氯甲基-5-三氟甲基苯、1-氯-4-氯甲基-2-硝基苯、4-氯甲基-1-甲基-2-硝基苯、2-氯甲基-1-甲基-4-硝基苯的合成,结果表明:选择氯磺酸为氯甲基化试剂和催化剂,最佳反应物配比:氯磺酸与含有吸电子基的芳香族化合物的摩尔比为0.9～1.1,多聚甲醛与含有吸电子基的芳香族化合物的摩尔比为1.1～1.5,反应效果最好。由于芳香烃苯环上取代基的性质各有不同,所以反应时间和温度也不近相同。通过对原料转化率数据和收率数据的比较和整理,以及对反应物摩尔比、反应温度、投料顺序、反应时间方面的考察,总结出含有吸电子基的芳香族化合物氯甲基化反应的规律,并得到最佳的反应条件。
最后,对所得主要产物进行~1HNMR和~(13)CNMR的结构表征以确定它们的结构。在这些化合物中,目标产物2-氯-5-氯甲基苯腈、1,2-二氯-3-氯甲基-5-三氟甲基苯、1-氯-4-氯甲基-2-硝基苯、4-氯甲基-1-甲基-2-硝基苯、2-氯甲基-1-甲基-4-硝基苯未见文献报道或未见用直接氯甲基化反应得到。
Blanc chloromethylation is a very classical reaction,which is a very important method on inducting chloromethyl in aryl hydrocarbon.It has very comprehensive application on the synthesis of pesticide、medicament、dye、spicery and other fine chemicals.The chloromethyl can be turned into many other groups,such as-CH_2OH、-CHO、-CH_2CN、-CH_2NH_2、-CH_3、-CH_2R and so on,which will be easily preparared for many new ramifications.
In this paper,the invention is concerned with a novel process for the chloromethylation of deactivated aromatic compounds.More particularly,this invention relates to a process for substituting an aromatic compound with a chloromethyl group by recting the aromatic compound with chlorosulfonic acid and para-formaldehyde.By the term "deactivated aromatic compound",as employed herein,is meant any organic compound having at least one benzenoid carbocyclic ring system with at least one electron-withdrawing substituting group and at least one replaceable hydrogen on the benzenoid ring system.In the classical Blanc chloromethylation,the influence factors and the mechanism of the reaction have also been studied.It was found that the reaction was accelerated obviously by the electron-donating substituting groups and decreased by the electron-withdrawing substituting groups.The process of this invention is especially effective for chloromethylating nitro-and trifluoromethylbenzenes because of their general resistance to direct chloromethylation with previously known chloromethylating agents.The reaction selectivity can be greatly improved,the outgrowth decreased and the yield can be obviously improved through emplying the new process to change the whole reactive system.So it decreased its disserve to our entironment and realized the friendly entironmental chloromethylation.
2-chloro-5-(chloromethyl)benzonitrile,1-chloro-2-(chloromethyl)-4-(trifluoro-methyl)benzene, 1,2-dichloro-3-(chloromethyl)-5-(trifluoromethyl)benzene,1-chloro-4-(chloromethyl)-2-nitrobenzene,4-(chloromethyl)-1-methyl-2-nitrobenzen,2-(chlor-omethyl)-1-methyl-4-nitrobenzene were synthesized by using this new process.Results indicated that when chlorosulfonic acid is chosen as the chloromethylating agent and catalyst,the molar ratio of reactants is not narrowly critical to the process.In general,it is preferred that the molar ratio of chlorosulfonic acid to benzene derivative with electron-withdrawing substituting group be approximately in the rang of from about 0.9 to about 1.1.On the other hand,it is generally preferred to employ an excess of para-formaldehyde,with from about 1.1 to about1.5 molar equivalents of formaldehyde per mol of benzene derivative being normally suitable.Because of the diverse characters of the groups on the benzenoid ring system,the temperatures and times of reaction are certainly dissimilar.By calculating the conversion of raw materials and yields of products and inspecting the possible factors affecting the reaction contained reaction temperature,reaction time,the regularity of chloromethylation of deactivated aromatic compounds is summarized.And the best condition employed by the new process is also screened.
Main products were compared with standard material,~1HNMR and ~(13)CNMR were used to make sure the molecular structure.Among these compounds,2-chloro-5-(chloromethyl)benzonitrile,1,2-dichloro-3-(chloromethyl)-5-(trifluoromethyl)benzene,1-chloro-4-(chloromethyl)-2-nitrobenzene,4-(chloromethyl)-1-methyl-2-nitrobenzen are new compounds or synthesized indirectly.
本文报道的这种方法是含有钝化基团的芳香化合物进行氯甲基化反应的新方法,即将芳香族化合物与氯磺酸和多聚甲醛反应,从而将氯甲基引入芳环。这里所说的芳香族化合物要含有至少一个含有吸电子基团的苯环和一个苯环上可被取代的氢。在经典的Blanc氯甲基化反应中,根据它的反应机理可得知:芳环上连有推电子基团时,有利于反应的进行;而连有强吸电子基团时,则不利于反应进行。而本文所报道的这种方法对于含硝基和三氟甲基的苯的氯甲基化反应是非常有效的,因为它们对以前报道过的氯甲基化试剂所进行直接氯甲基化反应是有阻碍作用的。通过采用这种新方法,改变了整个反应体系,无需再加入其它Lewis酸,反应选择性大为提高,副产物减少,收率明显得到提高。该反应减少了对环境的危害,实现了环境友好的氯甲基化反应。
采用这种新方法完成了2-氯-5-氯甲基苯腈、1-氯-2-氯甲基-4-三氟甲基苯、1,2-二氯-3-氯甲基-5-三氟甲基苯、1-氯-4-氯甲基-2-硝基苯、4-氯甲基-1-甲基-2-硝基苯、2-氯甲基-1-甲基-4-硝基苯的合成,结果表明:选择氯磺酸为氯甲基化试剂和催化剂,最佳反应物配比:氯磺酸与含有吸电子基的芳香族化合物的摩尔比为0.9～1.1,多聚甲醛与含有吸电子基的芳香族化合物的摩尔比为1.1～1.5,反应效果最好。由于芳香烃苯环上取代基的性质各有不同,所以反应时间和温度也不近相同。通过对原料转化率数据和收率数据的比较和整理,以及对反应物摩尔比、反应温度、投料顺序、反应时间方面的考察,总结出含有吸电子基的芳香族化合物氯甲基化反应的规律,并得到最佳的反应条件。
最后,对所得主要产物进行~1HNMR和~(13)CNMR的结构表征以确定它们的结构。在这些化合物中,目标产物2-氯-5-氯甲基苯腈、1,2-二氯-3-氯甲基-5-三氟甲基苯、1-氯-4-氯甲基-2-硝基苯、4-氯甲基-1-甲基-2-硝基苯、2-氯甲基-1-甲基-4-硝基苯未见文献报道或未见用直接氯甲基化反应得到。
Blanc chloromethylation is a very classical reaction,which is a very important method on inducting chloromethyl in aryl hydrocarbon.It has very comprehensive application on the synthesis of pesticide、medicament、dye、spicery and other fine chemicals.The chloromethyl can be turned into many other groups,such as-CH_2OH、-CHO、-CH_2CN、-CH_2NH_2、-CH_3、-CH_2R and so on,which will be easily preparared for many new ramifications.
In this paper,the invention is concerned with a novel process for the chloromethylation of deactivated aromatic compounds.More particularly,this invention relates to a process for substituting an aromatic compound with a chloromethyl group by recting the aromatic compound with chlorosulfonic acid and para-formaldehyde.By the term "deactivated aromatic compound",as employed herein,is meant any organic compound having at least one benzenoid carbocyclic ring system with at least one electron-withdrawing substituting group and at least one replaceable hydrogen on the benzenoid ring system.In the classical Blanc chloromethylation,the influence factors and the mechanism of the reaction have also been studied.It was found that the reaction was accelerated obviously by the electron-donating substituting groups and decreased by the electron-withdrawing substituting groups.The process of this invention is especially effective for chloromethylating nitro-and trifluoromethylbenzenes because of their general resistance to direct chloromethylation with previously known chloromethylating agents.The reaction selectivity can be greatly improved,the outgrowth decreased and the yield can be obviously improved through emplying the new process to change the whole reactive system.So it decreased its disserve to our entironment and realized the friendly entironmental chloromethylation.
2-chloro-5-(chloromethyl)benzonitrile,1-chloro-2-(chloromethyl)-4-(trifluoro-methyl)benzene, 1,2-dichloro-3-(chloromethyl)-5-(trifluoromethyl)benzene,1-chloro-4-(chloromethyl)-2-nitrobenzene,4-(chloromethyl)-1-methyl-2-nitrobenzen,2-(chlor-omethyl)-1-methyl-4-nitrobenzene were synthesized by using this new process.Results indicated that when chlorosulfonic acid is chosen as the chloromethylating agent and catalyst,the molar ratio of reactants is not narrowly critical to the process.In general,it is preferred that the molar ratio of chlorosulfonic acid to benzene derivative with electron-withdrawing substituting group be approximately in the rang of from about 0.9 to about 1.1.On the other hand,it is generally preferred to employ an excess of para-formaldehyde,with from about 1.1 to about1.5 molar equivalents of formaldehyde per mol of benzene derivative being normally suitable.Because of the diverse characters of the groups on the benzenoid ring system,the temperatures and times of reaction are certainly dissimilar.By calculating the conversion of raw materials and yields of products and inspecting the possible factors affecting the reaction contained reaction temperature,reaction time,the regularity of chloromethylation of deactivated aromatic compounds is summarized.And the best condition employed by the new process is also screened.
Main products were compared with standard material,~1HNMR and ~(13)CNMR were used to make sure the molecular structure.Among these compounds,2-chloro-5-(chloromethyl)benzonitrile,1,2-dichloro-3-(chloromethyl)-5-(trifluoromethyl)benzene,1-chloro-4-(chloromethyl)-2-nitrobenzene,4-(chloromethyl)-1-methyl-2-nitrobenzen are new compounds or synthesized indirectly.
引文
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[6]陈学恒.柠檬醛与苄氯制备缓释性香料的研究[J].江西化工,1998:29-32.
[7]Hafez M.A.H.,Kenawy I.M.M.,Akl M.A.,Lashein R.R:Preconcentration and separation of total mercury in environmental samples using chemically modified chloromethylated polystyrene PAN(ion-exchanger) and its determination by cold vapour atomic absorption spectrometry[J],Talanta,2001,53:749-760.
[8]Abdelaal M.Y.,Kenawyl.M.M,Hafez M.A.H.Chemical modification of chloromethylated polystyrene with pyridylazo-β-naphthol[J],Journal of Applied Polymer Science Journal of Applied Polymer Science,2000,77(14):3044-3048.
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[20]Huang Z T,Wang G Q,Yang L M.Synthesis of acetyl-substituted heterocyclic enamines and their reaction with diethyl azodicarboxylate[J].Synth.Commun.,1995,25(8):1339.
[21]Glaenzer B I,Csuk.Reaction of pyranoid aldnolactones with chioromethytrimethylsilane-derived reagents[J].Carbohydr.Res.,1991,220(11):79-92.
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[26]Weber H,Bier K.Process of preparing chloromethylated aromatic material[P].EP 0327255,1986.
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[29]Jerabek K,Setinek K C.Process for haloalkylation of high performance polymers[P].EP 0826700,1990.
[30]Takeya H,Octsuka H.Production process for1,4-naphthalene-dicarboxylic acid or 1-hydroxymethyl -4-napthoic acid[P].JP 05163198,1993.
[31]Kachurin O I,Okhrimenko Z A.Rotary razor-blade strop[P].US 1768573,1992.
[32]Maurwo Selva,Fransco Trotta,Pietro Tundo,Improved Selectivity in Chloromethylation of Alkylbenzenes in Presence of Quaternary Ammonia Salts[J],Synthesis,1991,(11),1003-1004.
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[2]Goto Y.,Sugimori S.,Ogawa T.,US.4797228,1989
[3]Plach H.,Hittich R.,Reifenrath V.,et al EP.460436,1991
[4]申东升,林原斌.农药增效剂胡椒基丁醚的合成研究[J],湘潭大学学报(自然科学版),1995,17(4):82-86.
[5]Dehaan F D,Djaputra M,Grinstaf M W,Kaufman C R,Electrophilic Aromatic Substitution.13.1 Kinetics and Spectroscopy of the Chloromethylation of Benzene and Toluene with Methoxyacetyl Chloride or Chloromethyl Methyl Ether and Aluminum Chloride in Nit romethane or Tin Tetrachloride in Dichloromethane.The Methoxymethyl Cation as a Rema rkably Selective Common Electrophile[J],J Org Chem.1997,62(9):2694.
[6]陈学恒.柠檬醛与苄氯制备缓释性香料的研究[J].江西化工,1998:29-32.
[7]Hafez M.A.H.,Kenawy I.M.M.,Akl M.A.,Lashein R.R:Preconcentration and separation of total mercury in environmental samples using chemically modified chloromethylated polystyrene PAN(ion-exchanger) and its determination by cold vapour atomic absorption spectrometry[J],Talanta,2001,53:749-760.
[8]Abdelaal M.Y.,Kenawyl.M.M,Hafez M.A.H.Chemical modification of chloromethylated polystyrene with pyridylazo-β-naphthol[J],Journal of Applied Polymer Science Journal of Applied Polymer Science,2000,77(14):3044-3048.
[9]Lyushin M,Hamada B.Deposited Doc.,1984,928.
[10]Ootsuka H,Takedya H.Synthesis and use of dimethyl 1,5-naphthalenedicarboxlyates and intermediates therefrom[P].JP 05117202,1993.
[11]Amato J S,Karady S,Sletzinger M,Weinstock L M.The synthesis of bicyclic and tricyclic ring systems by radical cyclisation reactions of oxime ethers[J],Synth.Commun.,1979,9(7):917.
[12]PoPov G,Haeupke K.DD 295564,1986.
[13]Pinnell R P,Khune G D,Khatri N A,Manatt S L.Concerning the chloromethylation of alkylbenzenes and polystyrenes by chloromethyl methyl ether[J],Tetrahedron lett.,1984,25(33):3511.
[14]Tashiro M,Nago H.Chem.Express.,1991,6(3):181.
[15]Tashiro M,Nago H.J.Chem.Res.Synop.,1990,(9):296.
[16]Warshawsky A.,Deshe A..Process for the Production of Halomethylating Agents Which are of Low Volatility[P],US 4568700,1986
[17]Greig J A,Sherrington D C.Molecular Sieve Behaviour In Polymeric Based Resins With Bound Nucleophilic Reagents[J].Eur.Polym.J.,1979,15(9):867-871.
[18]Naik H A,MC Grail P.T.,Maxkenzie P D,Pexrsons L W.Chemical modification of polyarylene ether/sulphone polymers:preparation and properties of materials aminated on the main chain[J].Polymer,1991,33(1):140-145.
[19]Almi M,Arduini A,Casnati A,Pochini A,Ungaro R.Chloromethylation of Calixarenes and Synthesis of New Water Solnble Macrocyclic Hosts[J].Tetrahedron,1989,45(7):2177.
[20]Huang Z T,Wang G Q,Yang L M.Synthesis of acetyl-substituted heterocyclic enamines and their reaction with diethyl azodicarboxylate[J].Synth.Commun.,1995,25(8):1339.
[21]Glaenzer B I,Csuk.Reaction of pyranoid aldnolactones with chioromethytrimethylsilane-derived reagents[J].Carbohydr.Res.,1991,220(11):79-92.
[22]N.K.Moshchinskaya,Chizh,G.K.and V.S.Oiifer,U.S.S.R.405:880,1974.
[23]Petrova R A,Berezin B D,Izv Vyssh,Uchebn Zaved Khim,Khim.Tekhnol.,1986,29(9),55.
[24]Barker P L,Bahia C.4-Chloromethylation of 1-methyl-2-pyrryl ketones[J].Tetrahedron,1990,46(8):2691-2694.
[25]Thomas P J,Pews R G.Process for preparing 3-chloromethylbenzo-cyclobutene[P].US 5099083,1991.
[26]Weber H,Bier K.Process of preparing chloromethylated aromatic material[P].EP 0327255,1986.
[27]明田耕一,西罔敏雄.日本公开特许,昭60 32750,1988.
[28]明田耕一,西罔敏雄.日本公开特许,昭60 32751,1988.
[29]Jerabek K,Setinek K C.Process for haloalkylation of high performance polymers[P].EP 0826700,1990.
[30]Takeya H,Octsuka H.Production process for1,4-naphthalene-dicarboxylic acid or 1-hydroxymethyl -4-napthoic acid[P].JP 05163198,1993.
[31]Kachurin O I,Okhrimenko Z A.Rotary razor-blade strop[P].US 1768573,1992.
[32]Maurwo Selva,Fransco Trotta,Pietro Tundo,Improved Selectivity in Chloromethylation of Alkylbenzenes in Presence of Quaternary Ammonia Salts[J],Synthesis,1991,(11),1003-1004.
[33]申东升,林原斌.3,4-亚甲二氧基正丙基苯的氯甲基化反应[J].合成化学,1997:5(2):202-204.
[34]Richter,Textbook of Organic Chemistry,pp.103 and 106(1938),John Wiley and Sons,New York,N.Y.
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