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1、經(jīng)典化學(xué)合成反應(yīng)標(biāo)準(zhǔn)操作脂肪鹵代物的合成1. 前言2. 脂肪族氯化物的制備2.1 醇的氯代2.11醇和氯化氫反應(yīng)的方法示例2.1.2醇和氯化亞砜的反應(yīng)2.1.3醇和氯化磷的反應(yīng)2.1.4醇和有機(jī)磷氯化物的反應(yīng)示例2.1.5醇和三苯基膦和四氯化碳加合物的反應(yīng)2.1.6醇和三苯基膦和六氯代丙酮加合物的反應(yīng)2.2 磺酸酯的氯置換反應(yīng)氯化鋰作為氯化劑的磺酸酯氯置換反應(yīng)2.3其他的一些制備脂肪族氯代烴的方法3. 脂肪族溴化物的制備3.1 醇的溴代3.1.1 醇和溴化氫反應(yīng)的方法示例3.1.2醇和氯化磷的反應(yīng)3.1.3醇和三苯基膦和四溴化碳加合物的反應(yīng)3.1.4 醇和三苯基膦和溴的加合物的反應(yīng)3.1.5醇
2、和三苯基膦和NBS加合物的反應(yīng)3.2磺酸酯或氯素的溴置換反應(yīng)例3.2.1 磺酸酯的溴置換反應(yīng)例3.2.2 氯素交換反應(yīng)3.3其他的一些制備脂肪族氯代烴的方法4. 脂肪族碘化物的制備經(jīng)典合成反應(yīng)標(biāo)準(zhǔn)操作脂肪鹵代物的合成4.1前言4.2 脂肪型醇的直接碘代4.2.1 (PhO)3P,CH3I體系4.2.2 Ph3P,I2,imidazole體系4.2.3 P,I2體系4.2.4 H3PO4,KI體系4.3脂肪型氯代物或溴代物的碘交換4.3.1 氯代物系列4.3.2 溴代物系列4.4 磺酸酯或鹵素素的碘置換反應(yīng)例4.5 其他的一些制備脂肪族碘代烴的方法5參考文獻(xiàn)Page9of421. 前言鹵代烴是不
3、僅是很多工業(yè)生產(chǎn)的重要產(chǎn)品,也是合成其他化合物的重要中間體,通過(guò)不同的反應(yīng)可以將鹵原子轉(zhuǎn)變成各種其他官能團(tuán),也可以進(jìn)行碳鏈的增長(zhǎng)。除了由烴基氫直接鹵代可得到鹵代烴外,還有很多種方法將其他的官能團(tuán)轉(zhuǎn)變成鹵代烴,如醇羥基鹵代,醛酮鹵代,羧酸脫羧后鹵代,磺酸酯的鹵素交換,有機(jī)金屬化合物鹵代。其中醇羥基的鹵置換反應(yīng)是制備鹵化物的重要方法,常用的鹵化試劑有氫鹵酸、含磷鹵化物和含硫鹵化物等,極大多數(shù)屬于醇羥基被鹵素負(fù)離子親核取代的機(jī)理。以下按照氯化物,溴化物,碘化物的制備分別加以討論。氟代烴的制備容以后討論2脂肪族氯化物的制備2.1 醇的氯代2.1.1醇與氯化氫反應(yīng)在親核取代反應(yīng)中,醇羥基的活性順序?yàn)槭辶u
4、基仲羥基伯羥基,芐位和烯丙位的羥基也很活波,這是由于碳正離子穩(wěn)定性差別的結(jié)果。同樣理由,活性較大的叔醇、芐醇的氯置換反應(yīng)傾向于SN1機(jī)理,而其他醇的反應(yīng),大多數(shù)以Sn2反應(yīng)機(jī)理為主。醇和HCl的反應(yīng)屬于可逆性平衡反應(yīng),其反應(yīng)難易程度取決于醇和HCl的濃度以及平衡點(diǎn)的移動(dòng)方向。若增加醇和HC1的濃度,以及能夠不斷移去產(chǎn)物和反應(yīng)生成的水,則均有利于加速氯置換反應(yīng)和提高收率。ROH+HXRX+H2O在醇的氯置換反應(yīng)中,活性較大的叔醇、芐醇等可以直接用濃鹽酸或氯化氫氣體,而伯醇常用盧卡斯試劑(濃煙酸-氯化鋅)進(jìn)行氯置換反應(yīng)。OHgasHCI-15min,r.t.CIyieId:97%2濃HC/ZnCJ
5、g八八Cyield:66%3OH4h,heatCI在某些仲醇、叔醇和0位具有叔碳取代基的伯醇的反應(yīng)中,若反應(yīng)溫度過(guò)高,會(huì)產(chǎn)生重排、異構(gòu)化和脫氯等副反應(yīng)。ExampleA:thepreparationoft-ButylChloride(2-Chloro-2-Methylpropane)OHHCICIIna250mlofseparatoryfunnelplace25g(0.34mol)of2-methylpropan-2-oland85mlofconcentratedhydrochloricacidandshakethemixturefromtimetotimeduring20min.Aftere
6、achshaking,loosenthestoppertorelieveanyinternalpressure.Allowthemixturetostandforafewminutesuntilthelayershaveseparatedsharply;drawoffanddiscardtheloweracidlayer.Washthehalidewith20mlof5%sodiumhydrogencarbonatesolutionandthenwith20mlofwater.Drythepreparationwith5gofanhydrouscalciumchlorideoranhydrou
7、scalciumsulphate.Decantthedriedliquidthroughafunnelsupportingaflutedfilterpaperintoa100mldistillingflaskanddistil.Collectthefractionboilingat49-51°C.Theyieldoft-butyl-chlorideis28g(90%).Ref:PracticalOrganicChemistry,4thedition,556ExampleB:thepreparationofButylChloride(1-Chlorobutane).宀宀OHHC/Zn%
8、ciFita250mlofround-bottomedflaskwitharefluxcondenser,thetopofwhichisconnectedtoadeviceforabsorbinghydrogenchloride.Place68g(0.5mol)ofanhydrouszincchlorideand40ml(47.5g)ofconcentratedhydrochloricacidintheflask,add18.5g(23ml,0.25mol)ofbutane-1-olandrefluxthemixturegentlyfor2hours.Arrangethecondenserfo
9、rdownwarddistillation,anddistilthereactionproduct,collectingthematerialwhichboilsbelow115C.Separatetheupperlayerofthedistillate,mixitwithanequalvolumeofconcentratedsulphuricacedandtransferthemixturetoa250mlofflaskfittedwitharefluxcondenser.Refluxgentlyfor15-30min,andthendistilthechloridefromtheacid;
10、itwillpassoverat76-79C.Washthedistillatesuccessivelywith25mlofwater,10mlof5%sodiumhydroxidesolutionand25mlifwater,dryover1-2gofanhydrouscalciumchloride,filteranddistilfromasmalldistillingflask.Collectthebutylchlorideat75-78C.Theyieldis15-16g(65-69%).Ref:PracticalOrganicChemistry,4thedition,5572.1.2醇
11、和氯化亞砜的反應(yīng)氯化亞砜是醇的氯置換反應(yīng)中一種常用的良好試劑,主要是反應(yīng)中生成的氯化氫和二氧化硫均為氣體,易揮發(fā)除去而無(wú)殘留物,經(jīng)直接蒸餾可得到純凈的氯代烴。醇和氯化亞砜的反應(yīng)過(guò)程,首先形成氯化亞硫酸酯(4),然后斷裂C-O鍵,釋放出二氧化硫生成氯代烴。(4)的分解方式與溶劑極性有關(guān),同時(shí)又決定了醇碳原子構(gòu)型在氯化反應(yīng)中的變化。如在二氧六環(huán)中反應(yīng),由于二氧六環(huán)的氧原子上未共用電子對(duì)從酯基的反位和酯碳原子形成微弱的鍵,增加了反位方向的位阻,促使氯離子作SNi取代,結(jié)果保留了醇碳原子原有的構(gòu)型;但是如果是在吡啶中反應(yīng)時(shí),由于氯化氫和吡啶成鹽而貯存于反應(yīng)液中,離解后的氯離子可從酯基的反應(yīng)作Sn2取代
12、,得到構(gòu)型翻轉(zhuǎn)的產(chǎn)物;如果沒(méi)有溶劑,在某些催化劑(如氯化鋅)作用下,(4)直接分解成離子對(duì)形式,于是按照SN1機(jī)理得到外消旋產(chǎn)物。4dioxaneOQClOH帝C例如,光學(xué)活性的2-正辛醇用氯化亞砜在不同溶劑中進(jìn)行反應(yīng),得到不同構(gòu)型的相應(yīng)氯化物,若添加氯化鋅作為催化劑,反應(yīng)速率明顯加快,SNi機(jī)理轉(zhuǎn)化為SN1機(jī)理得到外消旋產(chǎn)物。_H*H3CCC6H13OH*H*3C6H13Cl4SOCl2/benzene/r.t./16h(15%)(93%構(gòu)型翻轉(zhuǎn))SOCl2/dioxane/r.t./42h(100%)(82%構(gòu)型保留)SOCl2/dioxane/ZnCl2/r.t./1h(100%)(外消
13、旋混合物)烯丙醇和氯化亞砜在乙醚中進(jìn)行反應(yīng)時(shí),烯丙位重排產(chǎn)物的比例與所用的氯化亞砜濃度有關(guān)系。例如,化合物2-丁烯-1-醇(5)在5.6mol氯化亞砜醚溶液中得到兩種雙鍵位置不同的異構(gòu)體混合物;而用0.7mol氯化亞砜時(shí),幾乎完全得到重排產(chǎn)物,這可能由于在稀溶液中無(wú)水乙醚易和干燥氯化氫生成氫鍵連接的復(fù)合物,從而有利于SN1反應(yīng)和雙鍵重排。5OH5.6molSOCl2/Et2O(24%)(76%)0.7molSOCl2/Et2O(1%)(99%)在氯化亞砜的反應(yīng)中,若加入有機(jī)堿(如吡啶)作為催化劑,或者醇本身分子內(nèi)存在氨基等堿性基團(tuán),因能與反應(yīng)中生成的氯化氫結(jié)合,故有利于提高氯代反應(yīng)速率。此外,
14、該反應(yīng)也適宜于一些對(duì)酸敏感的醇類的氯置換反應(yīng)。例如,2-羥甲基四氫呋喃(6)用二氯亞砜和吡啶在室溫下反應(yīng),可得到預(yù)期的2-氯甲基四氫呋喃,而不影響酯環(huán)醚結(jié)構(gòu)。6SOCIdPyr.t.,3-4h5在SOC12和DMF或HMPA(催化劑兼溶劑)合用時(shí),其氯化劑的實(shí)際形式為(7)或(8)。由于它們具有活性大、反應(yīng)迅速、選擇性好以及能夠有效的結(jié)合反應(yīng)中生成的HCl等優(yōu)點(diǎn),故特別適宜于某些特殊要求的醇羥基氯置換反應(yīng),亦可作為良好的羧羥基氯置換試劑。SOCII口SOCIr詐、訃Me2NOCH2Me2N=CHCI】CI(Me2N)3PO(Me2N)2PCI=NMeJci78C8H7C6H4(OCH2CH2)
15、5OHSOCI2,DMFheat,15minC8H7C6H4(OCH2CH2)5CI(100%)6ExampleA:thepreparationof10-(4-Chlorobutyl)phenothiazineSOCI?Toasolutionof1(2.03g,7.5mmol)in100mlofdrybenzenewasaddeddropwisethionylchloride(2ml,10mmol).Themixturewasstirredatroomtemperatureovernight.Thesolventwasevaporatedtodrynessunderreducedpressur
16、e.Theresiduewasappliedonasilicagelcolumnandelutedwith10%ethylacetate/hexanestoyield2.17g(62%)of2.JournalofMedicinalChemistry,2002,45,13,2741-2748ExampleB:thepreparationof1-ChlorohexaneSOC2-.-OHClAssembleinafumecupboarda500mlthree-neckedflaskequippedwithasealedstirredunit,adoublesurfacerefluxcondense
17、randaseparatoryfunnel;fitthecondenserandthefunnelwithcalciumchlorideguard-tubes.Place179g(109.5ml,1.5mol)ofredistilledthionylchlorideintheflaskand51g(62.5ml,0.5mol)ofhexan-1-olintheseparatoryfunnel.Addtheacolholwithstirringduring2hours;theexcessevolutionofheat,sulphurdioxideisevolvedandtheliquiddark
18、ensconsiderably.Whenallthealcoholhasbeenadded,refluxthemixturefor2hours.Rearrangetheapparatusfordistillation,anddistilslowly;theexcessofthionylchloridepassesoverbelow80°C,followedbyasmallfractionupto120°C;andfinallythecrude1-chlorohexaneat132-134C.Washthelas-namedsuccessivelywithwater,10%s
19、odiumcarbonatesolution,andtwicewithwater.Drywithanhydrouscalciumchlorideanddistilthroughashortfractionatingcolumn.Pure1-chlorohexanepassesoverat133-134C.Theyieldis36g(60%).PracticalOrganicChemistry,4thedition,5582.1.3.醇和氯化磷的反應(yīng)用三氯化磷、五氯化磷對(duì)醇羥基做親核取代反應(yīng)也是經(jīng)典的氯置換反應(yīng)。這類氯化劑的活性比氫氯酸大,與后者相比,重排副反應(yīng)也較少。其中,三溴化磷和三氯化磷應(yīng)
20、用最多,前者效果比較好,也可以由溴和磷在反應(yīng)中直接生成,使用方便。三氯化磷和醇進(jìn)行反應(yīng)時(shí),首先生成亞磷酸的單、雙或三酯的混合物(9)和氯化氫,然后,由于傾向于形成磷?;≒=O)而使(9)中烷氧鍵發(fā)生斷裂,于是氯素負(fù)離子對(duì)酯分子中親電性烷基作親核取代反應(yīng),生成氯化物。ROH+PX3pORRX9上述親核取代過(guò)程,大多屬于sn2機(jī)理,因此,光學(xué)活性醇在與三氯化磷反應(yīng)后的主要產(chǎn)物常常為構(gòu)型翻轉(zhuǎn)的氯化物。但是,由于亞磷酸酯反應(yīng)的立體選擇性不高,故會(huì)發(fā)生一定比例的外消旋化。對(duì)于某些易發(fā)生重拍的醇(仲醇、0位具有叔碳取代基的伯醇等),由于SN1機(jī)理可能性增加,則隨著所用三氯化磷以及其用量、反應(yīng)條件不同,其
21、收率和重排副產(chǎn)物的比例也不同。五氯化磷和DMF反應(yīng)也生成氯代亞氨鹽(7)(Vilsmeier-Haack試劑),在二氧六環(huán)或者是乙腈等溶劑中和光學(xué)性仲醇(10)加熱反應(yīng),可得到高收率、構(gòu)型翻轉(zhuǎn)的氯代烴。PCl5+HCONMe2120C,15minMe2N=CHClci(88%)7Hn-C6H13COHCH310dioxaneorMeCN80-100C,3hHn-C6H13CClCH3119(84%-88%)(96.8%ee-99.6%ee)五氯化磷一般很少直接用于醇的氯代,但可以將酮或醛轉(zhuǎn)變成氯代烯烴。ExampleA:thepreparationofBenzyl-chloromethyl-3
22、-(quinolin-2-ylmethoxy)-phenylAsolutionof3-(2'-quinolylmethoxy)-N-benzyl-N-hydroxymethylaniline(8.4g)andphosphoroustrichloride(2.5ml)indichloromethane(100ml)isstirredatambienttemperaturefor24hoursandisthenwashedoncewithwater(100ml)andtwicewith5percentaqueoussodiumcarbonatesolution(200ml).Theorga
23、niclayerisseparated,driedovermagnesiumsulphateandevaporatedinvacuotogivethecrudetitlecompound,whichisusedinthefollowingstepwithoutfurtherpurification.US4826987A1(1989/05/02),ExampleB:Thepreparationof4-3-(Chloromethyl)phenylamino-6,7-dimethoxy-3-quinolinecarbonitrileHOPCl3ClTo14mlofDMFwasaddedphospho
24、roustrichloride(0.70ml,8.0mmol)withstirringat25-30.deg.C.After60m,themixturewascooledto0.deg.C.,andasuspensionof-3-(hydroxymethyl)phenylamino-6,7-dimethoxy-3-quinolinecarbonitrile(1.34g,4.0mmol)in6mlofDMFwasadded.Themixturewaswarmedto25.deg.C.,stirred15m,recooledinicebath,andpartitionedwithmethylene
25、chloride-aqueoussodiumbicarbonate.Theorganiclayerwaswashedwithwater,dried,andconcentratedtogive1.15gofanambersolid;NMR(CDC13)4.79(s,CH2C1).US6002008Al(1999/12/14),Appl.:US1998-49718(1998/03/27)ExampleC:Thepreparationof(E)-1-2-(2-bromo-4-chlorophenyl)-2-chloroethenyl-1H-imidazolemononitratePCl5,HAmix
26、tureof23.0partsof1-(2-bromo-4-chlorophenyl)-2-(1H-imidazol-1-yl)ethanone,23.0partsofpentachlorophosphoraneand17partsofphosphorylchloridewasstirredandrefluxedfor4hours.Thereactionmixturewascooledanddilutedwith260partsofdichloromethane.Thissolutionwasaddeddropwise,duringa2hoursperiod,toasolutionof300p
27、artsofpotassiumcarbonatein500partsofwater.Thewholewasstirredovernightatroomtemperature.Theproductwasextractedtwicewith2,2'-oxybispropane.Thecombinedextractsweredried,filteredandevaporated.Theresiduewasconvertedintothenitratesaltinethylacetateand2,2'-oxybispropane.Thesaltwasfilteredoffandpuri
28、fiedbyreversedphasechromatographyoverLiChroprep.RP18usingamixtureofmethanol(containing0.1percentofN-(1-methylethyl)-2-propanamine)andwater(containing0.5percentofammoniumacetate)(65:35byvolume)aseluent.Thefirstfractionwascollectedandtheeluentwasevaporated.Theresiduewasconvertedintothenitratesaltinami
29、xtureofethylacetateand2,2'-oxybispropane.Thesaltwasfilteredoffandcrystallizedfrom4-methyl-2-pentanone,yielding2.9parts(10percent)of(E)-1-2-(2-bromo-4-chlorophenyl)-2-chloroethenyl-1H-imidazolemononitrate;mp.162.9.deg.C.US4539325A1(1985/09/03)經(jīng)典合成反應(yīng)標(biāo)準(zhǔn)操作脂肪鹵代物的合成2.1.4醇和有機(jī)磷氯化物的反應(yīng)三苯膦氯化物,如Ph3PX2,PH3P+
30、CX3X-以及亞磷酸三苯酯氯化物如(PhO)3PX2、(PhO)3P+RX-,在和醇進(jìn)行氯置換反應(yīng)是,具有活性大,反應(yīng)條件溫和等特點(diǎn)。由于反應(yīng)中產(chǎn)生的氯化氫很少,因此不容易發(fā)生氯化氫引起的副反應(yīng)。三苯膦和六氯代丙酮(HCA)復(fù)合物和Ph3P/CCl4相似,也能將光學(xué)活性的烯丙醇在溫和條件下轉(zhuǎn)化成為構(gòu)型翻轉(zhuǎn)的烯丙氯代物,而且不發(fā)生異構(gòu)、重排等副反應(yīng)。這個(gè)試劑比Ph3P/CCl4更溫和,反應(yīng)迅速,特別適宜于用其他方法易引起重排的烯丙醇。OHPhgP/HCAf.CI(90%)12HDPh.P/HCA30C-r.t.,10minDHCl*(94%)(>99%構(gòu)型翻轉(zhuǎn))13Page24of42此外
31、,三苯膦或亞磷酸酯和N-氯代酰胺組成的復(fù)合氯化劑與上述試劑相似,但特別適宜于對(duì)酸不穩(wěn)定的醇或者是甾體醇的氯置換反應(yīng),也可用于缺電子的n體系的羥基氯置換。NBS/Ph3Por(PhO)3P.THF,r.t.,1hBrR(95%)14醇和有機(jī)磷氯化物的反應(yīng)示例ExampleA:ThepreparationofGeranylchlorideAdry,300-ml.,three-neckedflaskisequippedwithamagneticstirringbarandrefluxcondenser(towhichisattachedaDrierite-filleddryingtube)andch
32、argedwith90ml.ofcarbontetrachlorideand15.42g.ofgeraniol(0.1001mole).Tothissolutionisadded34.09g.(0.1301mole)oftriphenylphosphine,andthestirredreactionmixtureisheatedunderrefluxfor1hour.Thismixtureisallowedtocooltoroomtemperature;drypentaneisadded(100ml.),andstirringiscontinuedforanadditional5minutes
33、.Thetriphenylphosphineoxideprecipitateisfilteredandwashedwith50ml.ofpentane.Thesolventisremovedfromthecombinedfiltratewitharotaryevaporatorunderwateraspiratorpressureatroomtemperature.Distillationoftheresiduethrougha2-cm.Vigreuxcolumnattachedtoashort-pathdistillationapparatusprovides13.0-14.0g.(7581
34、%)ofgeranylchloride,b.p.4749°(0.4mm.),n23D=1.4794.OrganicSyntheses,Coll.Vol.6,p.634(1988);Vol.54,p.63(1974).ExampleB:Thepreparation5-(5-Chloropentyl)-5H-dibenzob,fazepinePPh3,CCI3COCCI3-Toacooled25mlround-bottomflaskcontaining1(50mg,0.16mmol)andPh3P(51mg,0.2mmol)wasaddedhexachloroacetone(HCA,0.
35、05ml,0.3mmol)in1mlofCH2Cl2.Thereactionmixturewasallowedtocometoroomtemperatureandstirredovernight.Themixturewassubjectedtopurificationbyflashsilicagelcolumnchromatography,withelutionfirstbyhexanetoremovetheHCAandthenby5%ethylacetate/hexanestogive49mg(93%)of2.JournalofMedicinalChemistry,2002,45,13,27
36、41-27482.1.5醇和其他氯化劑的反應(yīng)氯硅烷類試劑可以在溫和的條件下進(jìn)行醇羥基氯置換反應(yīng),高收率地得到氯代物。|°H昨心叫|C1(90%)15Bu30C,1.5hBuN-氯代酰胺與二甲硫醚反應(yīng)生成的氯代硫鎓鹽,對(duì)烯丙位或芐位的羥基的取代具有高度的選擇性,在低溫和中性條件下進(jìn)行反應(yīng),不會(huì)發(fā)生雙鍵的異構(gòu)化,且不影響脂肪族伯、仲羥基。DCM0C一SMeQO12H°_=lOH:1CDC1hHO16用四氯化錫也可在溫和的條件下高收率的將烯丙位、芐位羥基分別置換為溴和氯。r.t.,1h(93%)17(95%)四甲基-a-氯代烯胺(tetramethyl-a-haloenamine
37、s)(13)可將伯、仲羥基及烯丙位、芐位、炔丙位羥基在溫和的條件下轉(zhuǎn)化為相應(yīng)的氯代物。若將具有較大空間位阻的取代基替代氮原子上的甲基(14)或改用結(jié)構(gòu)類似物CMPA(chloro-phenylthio-methylene)dimethylammoniumchloride(15),則對(duì)伯羥基及烯丙位、芐位羥基的選擇性提高,特別是(15)不會(huì)影響底物結(jié)構(gòu)中存在的敏感基團(tuán)。13N14NClSPh15OH-3DCM,r.t.X=Cl(97%),X=Br(96%)18(94%)19HOHCl(88%)14(X=CI)DCM,r.t.RXN|2-氯代-3-乙基苯并噁唑四氟硼酸鹽(2-chloro-3-et
38、hylbenzoxazoliumtetrafluoroborate)(16),也為一較新發(fā)展的氯化劑,他是由鄰氨基苯酚在EtOCS2K和HCl作用下環(huán)合,再季銨化而制得。ClNH21FtOCS2K-NH22-HCIQBF4采用(16)對(duì)醇羥基進(jìn)行氯置換反應(yīng)的特點(diǎn)是在選用含不同氯素負(fù)離子的氨鹽條件下,將許多類型的醇包括甾體醇、糖類化合物等溫和地轉(zhuǎn)化成不同氯素取代的產(chǎn)物,并在大多數(shù)情況下發(fā)生了構(gòu)型翻轉(zhuǎn)。例如,在前列腺素合成中采用這個(gè)方法,以區(qū)域和立體選擇性地將前列腺素母體結(jié)構(gòu)(17)上三個(gè)羥基置換成所需構(gòu)型的不同氯素原子,得到關(guān)鍵中間體(18)。17醇和其他氯化劑的反應(yīng)的合成實(shí)例ExampleA:
39、ThepreparationBenzylChloridebyTMSCl/DMSO12A10mlflaskwaschargedwithamixtureof0.01mol(1.1g)ofbenzylalcoholand0.02mol(2.2g)ofTMSCl.Tothestirredsolutionwasadded0.2g(0.0026mmol)ofDMSOinasingleportion.Theflaskgrewwarmimmediately,ventedHCl(g)andwithin1minatwo-phasesystemhadformed.Themixturewasstirredforana
40、dditional10minandthendistilledthroughashort-pathmircoheadtoremovethevolatiles(81-98°C)andleave1.2 g(95%)ofproduct.J.Org.Chem.,1995,60,8,2638-26392.2 磺酸酯的氯置換反應(yīng)為了避免醇羥基在直接氯置換反應(yīng)中可能產(chǎn)生的副反應(yīng),可先將醇用磺酰氯轉(zhuǎn)化成為相應(yīng)的磺酸酯,再與親核性氯化試劑反應(yīng),生成所需的氯化烴。由于磺酰氯及其酯的活性較大,磺酰氯和氯置換反應(yīng)均在較溫和的條件下進(jìn)行,且常比氯素交換反應(yīng)更加有效。常用的氯化劑有氯化鈉、氯化鋰、氯化鎂等。反應(yīng)溶
41、劑為丙酮、醇、DMF等極性溶劑。MeSO2CI,LiCI一DMF,0C,1-1.5h磺酸酯的氯置換反應(yīng)合成示例ExampleA:ThepreparationGeranylchlorideMeLi,p-TsCI,LiCIHOHMPA-EtQ0CClAdry,1-L.,three-necked,round-bottomedflaskisequippedwithanoverheadmechanicalstirrer,a125-ml.pressureequalizingdroppingfunnelfittedwitharubberseptum,andanitrogeninlettube.Thesyst
42、emisflushedwithnitrogen,and15.4g.(0.100mole)ofgeraniol,35ml.ofdryhexamethylphosphorictriamide,100ml.ofanhydrousdiethylether,and50mg.oftriphenylmethaneareplacedintheflask.Thestirredsolutioniscooledto0°withanicebath,and63ml.(0.1mole)of1.6Mmethyllithiuminetherisinjectedintotheadditionfunnel.Themet
43、hyllithiumsolutionisaddeddropwiseoveraperiodof30minutes.Aftertheadditioniscomplete,thefunnelisrinsedbyinjecting5ml.ofdryether.Asolutionof20.0g.(0.105mole)ofp-toluenesulfonylchloridein100ml.ofanhydrousetherisinjectedintotheadditionfunnelandaddedoveraperiodof30minutestothestirred,red,0°reactionmi
44、xture.Theredcolorimmediatelydisappearsuponaddition.Afteradditioniscomplete,4.2g.(0.0990mole)ofanhydrouslithiumchlorideisadded.Thereactionmixtureiswarmedtoroomtemperatureandstirredovernight(18-20hours),duringwhichtimelithiump-toluenesulfonateprecipitates.Afteratotalof20-22hours,100ml.ofetherisadded,f
45、ollowedby100ml.ofwater.Thelayersareseparated,andtheorganicphaseiswashedfourtimeswith100-ml.portionsofwater,andfinallywith100ml.ofsaturatedsodiumchloride.Afterdryingtheorganicphaseoveranhydrousmagnesiumsulfate,thesolventisremovedonarotaryevaporator.Thecrudeproductistransferredtoa50-ml.flaskanddistill
46、edthrougha20-cm.Vigreuxcolumn,yielding14.114.6g.(8285%)ofgeranylchlorideasacolorlessliquid,b.p.7879°(3.0mm.).OrganicSyntheses,Coll.Vol.6,p.638;Vol.54,p.682.3 其他的一些制備脂肪族氯代烴的方法丙烯及芳烷基的a-氯代,醛酮,羧酸及酯的a-氯代,通過(guò)其他鹵代物如溴化物與KCl,BiCl反應(yīng),可以得到相應(yīng)的的氯化物,但由于一般情況下鹵代烴參與的取代反應(yīng)中,溴化物,碘化物比相應(yīng)的氯化物活潑,所以當(dāng)以鹵代烴作為中間體或原料時(shí),沒(méi)有必要將溴化
47、物,碘化物轉(zhuǎn)變?yōu)橄鄳?yīng)的氯化物。將烷基烴直接氯代,也是制備脂肪族氯代烴的方法,在此不一一列舉。31醇的溴代3.1.1醇和溴化氫反應(yīng)與醇和氯化氫反應(yīng)類似,醇也可以和氫溴酸反應(yīng)制備溴化物,而醇羥基的活性順序?yàn)槭辶u基仲羥基伯羥基,芐位和烯丙位的羥基也很活波,這是由于碳正離子穩(wěn)定性差別的結(jié)果。同樣理由活性較大的叔醇、芐醇的溴置換反應(yīng)傾向于SN1機(jī)理,而其他醇的反應(yīng),大多數(shù)以Sn2反應(yīng)機(jī)理為主。在某些仲醇、叔醇和0位具有叔碳取代基的伯醇的反應(yīng)中,若反應(yīng)溫度過(guò)高,會(huì)產(chǎn)生重排、異構(gòu)化和脫溴等副反應(yīng)。分子量小的伯醇可與氫溴酸及濃硫酸一起反應(yīng)。分子量比較大的伯醇溴代時(shí)可以將溴化氫通到加熱至100-110°
48、;C的醇中,可以直接得到溴代烷烴。醇和溴化氫反應(yīng)的方法示例:ExampleA:ThepreparationIsopropylBromide(2-bromopropane)Mixture40g(51ml,0.67mol)ofpropan-2-olwith460gofconstantboiling-pointhydrobromicacidina500mlflaskfittedwithadoublesurfacecondenser,addafewboilingchipsanddistilslowly(1-2dropspersecond)untilabouthalfoftheliquidhaspass
49、edover.Separatetheloweralkylbromidelayer(70g),andredistilltheaqueouslayerwhenafurther7gofthecrudebromidewillbeobtained.Shakethecrudebromideinaseparatoryfunnelsuccessivelywithanequalvolumeofconcentratedhydrochloricacid,water,5%sodiumhydrogencarbonatesolutionandwater,anddrywithanhydrouscalciumchloride
50、.Distilfroma100mlofflask;theisopropylbromidepassesoverat59°C.Theyieldis66g(81%).PracticalOrganicChemistry,4thedition,561ExampleB:ThepreparationofButylBromide(1-Bromobutane)HBr,H2SO4i'.-OHBrTo250gof48%hydrobromicacidcontainedina500mlroundbottomedflaskadd75g(41ml)ofconcentratedsulphuricacidin
51、portionswithshaking;somehydrogenbromidemaybeevolved.Add88g(110ml,1.2mol)ofbutan-1-olfollowedby60g(32.5ml)ofconcentratedsulphuricacidinseveralportionswithshaking,andfinallyafewchipsofporousporcelain.Attacharefluxcondensertotheflaskandrefluxthemixturegentlyfor2-3hours.Duringthisperiodtheformationofbut
52、ylbromideisalmostcompleteandalayerseparatesabovetheacid.Ifthepreparationiscarriedoutintheopenlaboratory,fitanabsorptiondevicetothetopofthecondenserinordertoabsorbanyhydrogenbromideandsulphurdioxidewhichmaybeevolved.Allowthecontentsoftheflasktocool,removethecondenserandsetitfordownwarddistillation,di
53、stilthemixtureuntilnomoreoilydropsofbutylbromidepassover(30-40min).Transferthedistillatetoaseparatoryfunnelandremovethehalidewhichformsthelowerlayer.Washitsuccessivelywithwater,anequalvolumeofconcentratedhydrochloricacid,water,5%sodiumhydrogencarbonateorsodiumcarbonatesolution,andwater.Separatethewa
54、terascompletelyaspossibleanddrywith2-3gofanhydrouscalciumchloride,thedesiccantshouldbeleftincontactwiththebromideforatleast30minandshakenoccasionally.Filterpaperintoa200mlofflaskanddistileitherfromanairbath.Collecttheportionboilingat100-103C.Theyieldis155g(95%).PracticalOrganicChemistry,4thedition,5
55、61-562ExampleC:ThepreparationdecamethylenebromideIIBHO-(CH;19OHaBr(Ch2)hf腳1鶉世A2-1.three-neckedflask,supportedinanoilbath,isfittedwithamechanicalstirrerandaninlettubewhichreachesalmosttothebottomoftheflask.Initisplaced696g.(4moles)ofdecamethyleneglycol,and,aftertheoilbathisheatedto9!-100°,arapid
56、streamofdryhydrogenbromideisintroduced,withstirring.Whenthemixturebecomessaturatedwiththegas,asshownbyvigorousfumingattheopenneckoftheflask(Note1),thetemperatureoftheoilbathisraisedto135°andaslowcurrentofhydrogenbromideispassedinfor6hours(Note2).Aftercooling,thecrudeproductistransferredtoasepar
57、atoryfunnelandtheloweraqueouslayerisdrawnoffanddiscarded.Theupperlayeriswashedoncewithanequalvolumeofwarmwaterandthenwithsuccessiveportionsof10滄odiumcarbonatesolutionuntilallacidhasbeenremoved.Itisthenwashedoncewithwarmwatewhichisseparatedascompletelyaspossible(Note3).TheproductthuswashedisdistilledfromaClaisenflaskunderreducedpressure.Thefirstfewdropsofdistillatecontainingsomewaterarediscarded:themainfractiondistilsat139142°/2mm.Theyieldis1080g.(90%(Note4).Reference:OrganicSyntheses,Col
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