脂肪卤代物的合成.docx

1、脂肪卤代物的合成经典化学合成反应标准操作脂肪卤代物的合成1. 前 言2. 脂肪族氯化物的制备2.1醇的氯代 2.1.1醇和氯化氢反应的方法示例2.1.2醇和氯化亚砜的反应2.1.3醇和氯化磷的反应2.1.4醇和有机磷氯化物的反应示例2.1.5醇和三苯基膦和四氯化碳加合物的反应2.1.6醇和三苯基膦和六氯代丙酮加合物的反应2.2 磺酸酯的氯置换反应氯化锂作为氯化剂的磺酸酯氯置换反应2.3其他的一些制备脂肪族氯代烃的方法3. 脂肪族溴化物的制备3.1 醇的溴代3.1.1醇和溴化氢反应的方法示例3.1.2醇和氯化磷的反应3.1.3醇和三苯基膦和四溴化碳加合物的反应3.1.4醇和三苯基膦和溴的加合物的

2、反应3.1.5醇和三苯基膦和NBS加合物的反应3.2磺酸酯或氯素的溴置换反应例3.2.1磺酸酯的溴置换反应例3.2.2氯素交换反应3.3其他的一些制备脂肪族氯代烃的方法4. 脂肪族碘化物的制备4.1 前言4.2 脂肪型醇的直接碘代 4.2.1 (PhO)3P, CH3I体系 4.2.2 Ph3P, I2, imidazole体系 4.2.3 P, I2体系 4.2.4 H3PO4, KI体系 4.3 脂肪型氯代物或溴代物的碘交换 4.3.1氯代物系列4.3.2溴代物系列 4.4磺酸酯或卤素素的碘置换反应例4.5其他的一些制备脂肪族碘代烃的方法5参考文献1. 前 言卤代烃是不仅是很多工业生产的重

3、要产品，也是合成其他化合物的重要中间体，通过不同的反应可以将卤原子转变成各种其他官能团，也可以进行碳链的增长。除了由烃基氢直接卤代可得到卤代烃外，还有很多种方法将其他的官能团转变成卤代烃，如醇羟基卤代，醛酮卤代，羧酸脱羧后卤代，磺酸酯的卤素交换，有机金属化合物卤代。其中醇羟基的卤置换反应是制备卤化物的重要方法，常用的卤化试剂有氢卤酸、含磷卤化物和含硫卤化物等，极大多数属于醇羟基被卤素负离子亲核取代的机理。以下按照氯化物，溴化物，碘化物的制备分别加以讨论。氟代烃的制备容以后讨论2脂肪族氯化物的制备2.1 醇的氯代2.1.1醇与氯化氢反应在亲核取代反应中，醇羟基的活性顺序为叔羟基仲羟基伯羟基，苄位

4、和烯丙位的羟基也很活波，这是由于碳正离子稳定性差别的结果。同样理由，活性较大的叔醇、苄醇的氯置换反应倾向于SN1机理，而其他醇的反应，大多数以SN2反应机理为主。醇和HCl的反应属于可逆性平衡反应，其反应难易程度取决于醇和HCl的浓度以及平衡点的移动方向。若增加醇和HCl的浓度，以及能够不断移去产物和反应生成的水，则均有利于加速氯置换反应和提高收率。在醇的氯置换反应中，活性较大的叔醇、苄醇等可以直接用浓盐酸或氯化氢气体，而伯醇常用卢卡斯试剂（浓烟酸-氯化锌）进行氯置换反应。在某些仲醇、叔醇和位具有叔碳取代基的伯醇的反应中，若反应温度过高，会产生重排、异构化和脱氯等副反应。Example A:

5、the preparation of t-Butyl Chloride (2-Chloro-2-Methylpropane)In a 250 ml of separatory funnel place 25 g (0.34 mol) of 2-methylpropan-2-ol and 85 ml of concentrated hydrochloric acid and shake the mixture from time to time during 20 min. After each shaking, loosen the stopper to relieve any interna

6、l pressure. Allow the mixture to stand for a few minutes until the layers have separated sharply; draw off and discard the lower acid layer. Wash the halide with 20 ml of 5% sodium hydrogen carbonate solution and then with 20 ml of water. Dry the preparation with 5 g of anhydrous calcium chloride or

7、 anhydrous calcium sulphate. Decant the dried liquid through a funnel supporting a fluted filter paper into a 100 ml distilling flask and distil. Collect the fraction boiling at 49-51. The yield of t-butyl-chloride is 28 g (90%).Ref: Practical Organic Chemistry, 4th edition, 556Example B: the prepar

8、ation of Butyl Chloride (1-Chlorobutane)Fit a 250 ml of round-bottomed flask with a reflux condenser, the top of which is connected to a device for absorbing hydrogen chloride. Place 68 g (0.5 mol) of anhydrous zinc chloride and 40 ml (47.5 g) of concentrated hydrochloric acid in the flask, add 18.5

9、 g (23 ml, 0.25 mol) of butane-1-ol and reflux the mixture gently for 2 hours. Arrange the condenser for downward distillation, and distil the reaction product, collecting the material which boils below 115. Separate the upper layer of the distillate, mix it with an equal volume of concentrated sulp

10、huric aced and transfer the mixture to a 250 ml of flask fitted with a reflux condenser. Reflux gently for 15-30 min, and then distil the chloride from the acid; it will pass over at 76-79. Wash the distillate successively with 25 ml of water, 10 ml of 5% sodium hydroxide solution and 25 ml if water

11、, dry over 1-2 g of anhydrous calcium chloride, filter and distil from a small distilling flask. Collect the butyl chloride at 75-78. The yield is 15-16 g (65-69%). Ref : Practical Organic Chemistry, 4th edition, 5572.1.2 醇和氯化亚砜的反应氯化亚砜是醇的氯置换反应中一种常用的良好试剂，主要是反应中生成的氯化氢和二氧化硫均为气体，易挥发除去而无残留物，经直接蒸馏可得到纯净的氯代

12、烃。醇和氯化亚砜的反应过程，首先形成氯化亚硫酸酯(4)，然后断裂C-O键，释放出二氧化硫生成氯代烃。(4)的分解方式与溶剂极性有关，同时又决定了醇碳原子构型在氯化反应中的变化。如在二氧六环中反应，由于二氧六环的氧原子上未共用电子对从酯基的反位和酯碳原子形成微弱的键，增加了反位方向的位阻，促使氯离子作SNi取代，结果保留了醇碳原子原有的构型；但是如果是在吡啶中反应时，由于氯化氢和吡啶成盐而贮存于反应液中，离解后的氯离子可从酯基的反应作SN2取代，得到构型翻转的产物；如果没有溶剂，在某些催化剂（如氯化锌）作用下，(4)直接分解成离子对形式，于是按照SN1机理得到外消旋产物。例如，光学活性的2-正辛

13、醇用氯化亚砜在不同溶剂中进行反应，得到不同构型的相应氯化物，若添加氯化锌作为催化剂，反应速率明显加快，SNi机理转化为SN1机理，得到外消旋产物。烯丙醇和氯化亚砜在乙醚中进行反应时，烯丙位重排产物的比例与所用的氯化亚砜浓度有关系。例如，化合物2-丁烯-1-醇(5)在5.6 mol 氯化亚砜醚溶液中得到两种双键位置不同的异构体混合物；而用0.7 mol氯化亚砜时，几乎完全得到重排产物，这可能由于在稀溶液中无水乙醚易和干燥氯化氢生成氢键连接的复合物，从而有利于SN1反应和双键重排。在氯化亚砜的反应中，若加入有机碱（如吡啶）作为催化剂，或者醇本身分子内存在氨基等碱性基团，因能与反应中生成的氯化氢结合

14、，故有利于提高氯代反应速率。此外，该反应也适宜于一些对酸敏感的醇类的氯置换反应。例如，2-羟甲基四氢呋喃(6)用二氯亚砜和吡啶在室温下反应，可得到预期的2-氯甲基四氢呋喃，而不影响酯环醚结构。在SOCl2和DMF或HMPA（催化剂兼溶剂）合用时，其氯化剂的实际形式为（7）或（8）。由于它们具有活性大、反应迅速、选择性好以及能够有效的结合反应中生成的HCl等优点，故特别适宜于某些特殊要求的醇羟基氯置换反应，亦可作为良好的羧羟基氯置换试剂。Example A: the preparation of 10-(4-Chlorobutyl)phenothiazineTo a solution of 1

15、(2.03 g, 7.5 mmol) in 100 ml of dry benzene was added dropwise thionyl chloride (2 ml, 10 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated to dryness under reduced pressure. The residue was applied on a silica gel column and eluted with 10% ethyl acetate/hexan

16、es to yield 2.17 g (62%) of 2.Journal of Medicinal Chemistry, 2002, 45, 13, 2741-2748Example B: the preparation of 1-ChlorohexaneAssemble in a fume cupboard a 500 ml three-necked flask equipped with a sealed stirred unit, a double surface reflux condenser and a separatory funnel; fit the condenser a

17、nd the funnel with calcium chloride guard-tubes. Place 179 g (109.5 ml, 1.5 mol) of redistilled thionyl chloride in the flask and 51 g (62.5 ml, 0.5 mol) of hexan-1-ol in the separatory funnel. Add the acolhol with stirring during 2 hours; the excess evolution of heat, sulphur dioxide is evolved and

18、 the liquid darkens considerably. When all the alcohol has been added, reflux the mixture for 2 hours. Rearrange the apparatus for distillation, and distil slowly; the excess of thionyl chloride passes over below 80, followed by a small fraction up to 120; and finally the crude 1-chlorohexane at 132

19、-134. Wash the las-named successively with water, 10% sodium carbonate solution, and twice with water. Dry with anhydrous calcium chloride and distil through a short fractionating column. Pure 1-chlorohexane passes over at 133-134. The yield is 36 g (60%). Practical Organic Chemistry, 4th edition, 5

20、582.1.3. 醇和氯化磷的反应用三氯化磷、五氯化磷对醇羟基做亲核取代反应也是经典的氯置换反应。这类氯化剂的活性比氢氯酸大，与后者相比，重排副反应也较少。其中，三溴化磷和三氯化磷应用最多，前者效果比较好，也可以由溴和磷在反应中直接生成，使用方便。三氯化磷和醇进行反应时，首先生成亚磷酸的单、双或三酯的混合物（9）和氯化氢，然后，由于倾向于形成磷酰基（P=O）而使（9）中烷氧键发生断裂，于是氯素负离子对酯分子中亲电性烷基作亲核取代反应，生成氯化物。上述亲核取代过程，大多属于SN2机理，因此，光学活性醇在与三氯化磷反应后的主要产物常常为构型翻转的氯化物。但是，由于亚磷酸酯反应的立体选择性不高，故会

21、发生一定比例的外消旋化。对于某些易发生重拍的醇（仲醇、位具有叔碳取代基的伯醇等），由于SN1机理可能性增加，则随着所用三氯化磷以及其用量、反应条件不同，其收率和重排副产物的比例也不同。五氯化磷和DMF反应也生成氯代亚氨盐（7）（Vilsmeier-Haack试剂），在二氧六环或者是乙腈等溶剂中和光学性仲醇（10）加热反应，可得到高收率、构型翻转的氯代烃。五氯化磷一般很少直接用于醇的氯代，但可以将酮或醛转变成氯代烯烃。Example A: the preparation of Benzyl-chloromethyl-3-(quinolin-2 -ylmethoxy)-phenyl -amine

22、A solution of 3-(2-quinolylmethoxy)-N-benzyl-N-hydroxymethylaniline (8.4 g) and phosphorous trichloride (2.5 ml) in dichloromethane (100 ml) is stirred at ambient temperature for 24 hours and is then washed once with water (100 ml) and twice with 5percent aqueous sodium carbonate solution (200 ml).

23、The organic layer is separated, dried over magnesium sulphate and evaporated in vacuo to give the crude title compound, which is used in the following step without further purification.US4826987 A1 (1989/05/02), Example B: The preparation of 4-3-(Chloromethyl)phenylamino-6,7- dimethoxy-3- quinoline

24、carbonitrile To 14 ml of DMF was added phosphorous trichloride (0.70 ml, 8.0 mmol) with stirring at 25-30.deg. C. After 60 m, the mixture was cooled to 0.deg. C., and a suspension of -3-(hydroxymethyl)phenylamino-6,7-dimethoxy-3-quinolinecarbonitrile (1.34 g, 4.0 mmol) in 6 ml of DMF was added. The

25、mixture was warmed to 25.deg. C., stirred 15 m, recooled in ice bath, and partitioned with methylene chloride-aqueous sodium bicarbonate. The organic layer was washed with water, dried, and concentrated to give 1.15 g of an amber solid; NMR (CDCl3) 4.79(s, CH2Cl). US6002008 A1 (1999/12/14), Appl.: U

26、S1998-49718 (1998/03/27)Example C: The preparation of (E)-1-2-(2-bromo-4-chlorophenyl) -2-chloroethenyl-1H-imidazole mononitrate A mixture of 23.0 parts of 1-(2-bromo-4-chlorophenyl)-2- (1H-imidazol-1-yl) ethanone, 23.0 parts of pentachlorophosphorane and 17 parts of phosphoryl chloride was stirred

27、and refluxed for 4 hours. The reaction mixture was cooled and diluted with 260 parts of dichloromethane. This solution was added dropwise, during a 2 hours period, to a solution of 300 parts of potassium carbonate in 500 parts of water. The whole was stirred overnight at room temperature. The produc

28、t was extracted twice with 2,2-oxybispropane.The combined extracts were dried, filtered and evaporated. The residue was converted into the nitrate salt in ethyl acetate and 2,2-oxybispropane. The salt was filtered off and purified by reversed phase chromatography over LiChroprep. RP 18 using a mixtu

29、re of methanol (containing 0.1percent of N-(1-methylethyl)-2-propanamine) and water (containing 0.5percent of ammonium acetate) (65:35 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was converted into the nitrate salt in a mixture of ethyl acetate a

30、nd 2,2-oxybispropane. The salt was filtered off and crystallized from 4-methyl-2-pentanone, yielding 2.9 parts (10percent) of (E)-1-2-(2-bromo-4-chlorophenyl) -2-chloroethenyl-1H-imidazole mononitrate; mp. 162.9.deg. C. US4539325 A1 (1985/09/03)2.1.4 醇和有机磷氯化物的反应三苯膦氯化物，如Ph3PX2, PH3P+CX3X- 以及亚磷酸三苯酯氯化物

31、如(PhO)3PX2、(PhO)3P+RX-，在和醇进行氯置换反应是，具有活性大，反应条件温和等特点。由于反应中产生的氯化氢很少，因此不容易发生氯化氢引起的副反应。三苯膦和六氯代丙酮（HCA）复合物和Ph3P/CCl4相似，也能将光学活性的烯丙醇在温和条件下转化成为构型翻转的烯丙氯代物，而且不发生异构、重排等副反应。这个试剂比Ph3P/CCl4更温和，反应迅速，特别适宜于用其他方法易引起重排的烯丙醇。此外，三苯膦或亚磷酸酯和N-氯代酰胺组成的复合氯化剂与上述试剂相似，但特别适宜于对酸不稳定的醇或者是甾体醇的氯置换反应，也可用于缺电子的体系的羟基氯置换。 醇和有机磷氯化物的反应示例 Exampl

32、e A: The preparation of Geranyl chlorideA dry, 300-ml., three-necked flask is equipped with a magnetic stirring bar and reflux condenser (to which is attached a Drierite-filled drying tube) and charged with 90 ml. of carbon tetrachloride and 15.42 g. of geraniol (0.1001 mole). To this solution is added 34.09 g. (0.1301 mole) of triphenylphosphine, and the stirred reaction mixture is heated under reflux for 1 hour. T