华科分析药理课件-有机化学chapter14含氮

AminesCompoundscontainingNitrogenatom本章内容；1、硝基化合物(nitrocompounds)2、胺(amines)3、季铵盐和季铵碱(Quaternary

Saltsand

QuaternaryAmmoniumHydroxides)4、重氮化合物与偶氮化合物

(diazoandazocompounds)第一节、硝基化合物硝基化合物(nitrocompounds)是指烃分子中的氢原子被硝基(－NO2)nitro-group取代后得到的化合物，一元硝基化合物常用RNO2或ArNO2表示。ExampleNitrocompoundsNitriteester硝基化合物亚硝酸酯Structure127O122pm122pm硝基中，氮原子为sp2杂化氮原子上未杂化的p轨道和两个氧原子上的p轨道互相重叠，形成包括三个原子在内三中心四电子的大π键分子轨道：Nomenclature与卤烃相类似，以烃为母体，硝基作为取代基。例如：

nitroethane

2-nitropropane

4-nitrotoluene2,4,6-trinitrotoluene

Chenmicaireaction1.有关硝基对α-H影响的反应(1)酸性Why?Goodnucleophilicreagent硝基式假酸式酸性和互变异构具有α氢的硝基化合物与强碱作用生成盐：含α氢的1°和2°脂肪族硝基化合物能逐渐溶于强碱的水溶液中并形成盐，表现出明显的酸性。一般认为这是由于这些硝基化合物中存在着下列互变异构现象：(2)缩合反应2.硝基对邻、对位取代基活性的影响

加成消除机理使甲基的氢易离去3.硝基的还原在碱性介质中发生双分子还原在中性介质中生成苯基羟胺选择性还原Impossibletopredictwhichnitrogroupwillbereduced

AminesAminesareusedin…杀虫剂Pesticide染料Dye制药Manufacturesdrugs聚合物PolymerAminesare…氨的衍生物(NH3).它既是碱又是酸第二节、胺类SomeExamplescocaine

3°aminestreucturecocainecocaine

plantcocaine

flower

苯丙胺类兴奋剂均具有中枢神经系统兴奋作用，但不同药物的作用各有侧重amphetamine

NicotineCaffeineProcaine胺是氨的衍生物ammoniaamine

derivatives1º2º3ºPrimaryamineSecondaryamineTertiaryaminequaternary

salt1.Classification:可为aliphatic,aromatic,andhetero-cyclicamines:aliphaticamines:氮直接连接在脂基上aromaticamines:氮直接连接在芳基上heterocyclicamines:氮在环中2.Nomenclaturemethylamine

ethylamine

cyclohexylaminetert-butylamine1).Primaryamines(RNH2)arenamedbyaddingtheword“amine”tothenameoftheRgroup.PrimaryaminescanbenamedinIUPACsystemintwoways2).analogoustoalcohols:replace-eendingby-amineCH3CH2NH2ethanamineNH2cyclohexanamineCH3CHCH2CH2CH3NH22-pentanamine3)NomenclatureofPrimaryArylamines(ArNH2)NameasderivativesofanilineNH2只有当氨基直接连接在芳环上才是芳香胺

Examples:someprimaryarylamines(ArNH2:onecarbondirectlyattachedtoN)p-fluoroaniline5-bromo-2-ethylanilineNH2FNH2BrCH2CH3AminogroupsassubstituentsaminogroupsrankbelowOHgroupsandhigheroxidationstatesofcarboninsuchcasesnametheaminogroupasasubstituentp-aminobenzaldehydeNH2HCOHOCH2CH2NH22-aminoethanoldimethylamine

triethylamine

dicyclohexylamineSymmetricalsecondary(R2NH)andtertiaryamines(R3N)arenamedbyadding“di-”or“tri-”asprefixestothenameoftheRgroup.N-methylethylamine

N-methyldiethylamine

N,N-dimethylethylamineUnsymmetricalsecondary(RR’NH)andtertiaryamines(RR’R”N)arenamedasN-substitutedprimaryamines.ThelargestRgroupdeterminesthenameoftheamine.N-ethyl-N-methylpropylamineExamplesCH3NHCH2CH3N-methylethylamineNHCH2CH3NO2Cl4-chloro-N-ethyl-3-nitroanilineCH3NCH3N,N-dimethylcycloheptylamineAmmoniumSaltsAnitrogenwithfoursubstituentsispositively

chargedandisnamedasaderivativeof

ammoniumion(NH4+).CH3NH3+Cl–methylammonium

chlorideNCH3HCH2CH3+CF3CO2–N-ethyl-N-methylcyclopentylammonium

trifluoroacetateAmmoniumSaltsWhenallfouratomsattachedtoNarecarbon,

theioniscalledaquaternaryammoniumionand

saltsthatcontainitarecalledquaternary

ammoniumsalts.+CH2NCH3CH3CH3I–benzyltrimethylammoniumiodide3.Structure147pm112106Alkylamines甲胺的结构

胺具有棱锥形的结构.Theaminestructureandtheammoniaaresimilar.

nitrogenatomissp3hybridization,

theamineasthetetrahedralstructure,nitrogenatomseemstobeaschiralatoms.simpleamineenantiomersresolutiondidnotsucceed.氨、甲胺和三甲胺的结构如下：Aromaticaminesarealsosp3hybridization，nitrogenatombondedwiththecarbonatomsofsp2

hybridcarbon，alsomakesthenitrogenatomasthecenterofthetetrahedron,thealiphaticaminesareintheflatshape，porbitalofthenitrogenconjugatedwiththebenzenering.Structureofaniline

INVERSIONOFSMALLAMINESIffastinversionoccurs,apyrimidalnitrogenwillnotbeanactivestereocenter.RACEMICMIXTUREOFENANTIOMERS手性季铵盐正离子，可以被拆开成对映体。activestereocenterBICYCLICAMINESAREUSUALLYRIGID

CH3HTheringscannotinvert.******Thenitrogenisrigidlyheldinthebicyclicringsandcannotinvert.(1)BasicityofAmines

Inaqueousalkalinesequenceofaliphaticissecondaryamine>primaryamine>tertiaryamine,(CH3)2NH>CH3NH2>(CH3)3N>NH3measuredinthegasphase,aminebasicsequenceisatertiaryamine>secondaryamines>primaryamine.

4.ChemicalPropertiesIfweconsideronlythesolvationeffectofdifferentamine,thebasicordershouldbeprimaryamine>secondaryamine>tertiaryamine.

Therefore,theoverallevaluationaboveinfluencealkalinitythreekindoffactors(electroniceffect,solvationeffectandspatialeffect),intheaqueoussolution,thesecondaryaminealkalinityarestrongest,butprimaryamineandtertiaryaminearenext.

C6H5NH2(C6H5)2NH(C6H5)3NKb3.8x10-106x10-14~10-19Thealkalinityofaromaticamineismuchweakerthantheammonia,thisisbecauseintheanilineinthenitrogenwithpairofunsharedelectronhastheconjugationwiththebenzenering,reducedonthenitrogenatomelectrondensity,causesitsalkalinitytoweakengreatly.

PhNH2>Ph2NH>Ph3NEffectofsubstituents①

Forthevastmajorityofsubstituents,whetheritiselectron-donatinggroupsorelectron-withdrawinggroups,inortho-substituentsaregenerallyreducedtoalkaline(inthetable,excepttoOH).PhNH2>>>pKa4.624.392.70-0.3②

electron-donatinggroupsenhancedthealkaline,electron-withdrawinggroupstoweaken;在对位比在间位更为明显。③Forthetwoeffectsofonegroups,itsimpactdependsontwokindofeffectthedirectionandrelativestrength.

Speakingofthechlorine,itisintheaminothepara-position,alsohasattractselectronictheinductiveeffectandfortheelectronicconjunctiveeffect,butitsconjunctiveeffectmustweaklyintheinductiveeffect,thereforethealkalinitywillbeweaken,Buthalogeninthemeta-position,onlytheelectronwithdrawinginductiveeffectatwork,sothealkalinitydeclinemore.

PhNH2pKa4.003.48

芳香胺的碱性比氨和脂胺弱得多，这是因为氮上未共用电子对与苯环有共轭作用，分散了氮上的这一对电子，使其碱性大大减弱。在芳胺中，氮上的氢原子若被烷基取代，会使碱性增强。如：PhN(CH3)2>PhNHCH3>PhNH2芳胺和脂胺的碱性比较芳脂胺的碱性大于芳胺。季铵碱因在水中可完全电离,因此是强碱,其碱性与氢氧化钾相当。Butthemethoddoesn'tworkwellinpractice.

Usuallygivesamixtureofprimary,secondary,

andtertiaryamines,plusthequaternarysalt.

AlkylationofAmmonia（2）AlkylationExampleAsoctylamineisformed,itcompeteswithammoniafortheremaining1-bromooctane.Reactionofoctylaminewith1-bromooctanegivesN,N-dioctylamine.CH3(CH2)6CH2BrNH3CH3(CH2)6CH2NH2(45%)+CH3(CH2)6CH2NHCH2(CH2)6CH3(43%)

（3）Acylation

Conversionofaminesintosubstituted

amidesammoniareactswithacidchloridesandsulfonylchlorides

酰化磺酰化primaryandsecondaryaminescanalsoreactwithacidchloridestoformsubstitutedamides.Buttertiaryaminesfailtoyieldamides.

Application①.Analysisofamines.HinsbergtestApplication②.Protecttheaminogroupinsynthesis③.SynthesisofSulfanilamide:Thesulfadrugs（4）ReactionsofAmineswithnitrousacid①.Diazotizationreaction：Reactionsof

PrimaryArylamines

withNitrousAcidStructureofarenediazoniumsaltsReactionsMechanismofPrimaryArylamineswithNitrousAcidReactionsofPrimaryAliphaticAmineswithNitrousAcid定量放出氮气测定－NH2的量混合物无制备价值Ring-expansionreaction；可用于制备五至九元的环酮。例如：②．Reactionsof

SecondaryAmines

withNitrousAcid

obtain

N-nitrosoamines.例如：SolidoryellowcompoundactsasidentificationN-Nitrosoamines:Verypowerfulcarcinogens,maybepresentinmanyfoods,especiallyincookedmeats③.Reactionsof

TertiaryAmines

with

NitrousAcidUnstableproductColorproductcanidentifyAraminesArylamines;

（5）ElectrophilicAromatic

Substitution

inArylamines①.Nitrationoccursreadilywithoutnecessityofprotecting

aminogroup,butdifficulttolimitittomonohalogenation硫酸氨基是间位定位基乙酰氨基是邻对位定位基②.HalogenationofArylamines反应定量完成，可用作定性、定量分析。③.Friedel-CraftsReactionsTheaminogroupofanarylaminemustbeprotectedasanamidewhencarryingoutaFriedel-Craftsreaction.NHCCH3OCH2CH3CH3CClOAlCl3(57%)NHCCH3OCCH3OCH2CH3④.Sulfonationreaction

rearrangment磺胺类药物母体磺化氯磺化

Section3Quaternary

Saltsand

QuaternaryAmmoniumHydroxides

Phase-TransferCatalystsPhase-TransferCatalysisQuaternaryammoniumsaltsarephase-transfer

catalysts.Theyaresolubleinnonpolarsolvents.NH3CCH2CH2CH2CH2CH2CH2CH2CH3CH2CH2CH2CH2CH2CH2CH2CH3CH2CH2CH2CH2CH2CH2CH2CH3+Cl–Methyltrioctylammonium

chloridePhase-TransferCatalysisCl–BenzyltriethylammoniumchlorideNCH2CH3CH2CH3CH2CH3+ExampleTheSN2reactionofsodiumcyanidewithbutyl

bromideoccursmuchfasterwhenbenzyl-

triethylammoniumchlorideispresentthanwhen

itisnot.CH3CH2CH2CH2Br+NaCNCH3CH2CH2CH2CN+NaBrBenzyltriethylammoniumchloride

The

HofmannElimination(positionofquaternaryammoniumhydroxide)Hofmann,AugustWilhelm

Born:Giessen(Germany),1818

Died:Berlin(Germany),18921.TheaminetreatedwithexcessmethyliodidetoconvertittothequaternaryammoniumiodideHofmannexclusivemethylation2.Converttheiodidetohydroxidebysilveroxide3.Heatingthedryquaternaryammoniumhydroxide

MechanismRegioselectivityheatEliminationoccursinthedirectionthatgives

theless-substituteddoublebond.Thisiscalled

theHofmannrule.N(CH3)3+HO–CH3CHCH2CH3H2CCHCH2CH3CH3CHCHCH3+(95%)(5%)Regioselectivity

N(CH3)3+HHHHCH3CH2CHCHHCH3CH2largestgroupisbetweentwoHatomsmajorproductTheHofmannElimination

aquaternaryammoniumhydroxideisthereactantandanalkeneistheproductisan

antielimination，theleavinggroupisatrialkylamine，theregioselectivityis

oppositetotheZaitsevrule.

Example

ExampleSection4、DiazoandAzocompounds1.DiazoCompounds制备；芳香族伯胺与亚硝酸在低温下反应，生成重氮盐。TransformationsofArylDiazoniumSaltsArNN+ArHArOHArIArFArBrArClArCNExample①2.H2O,heat(CH3)2CHNH21.NaNO2,H2SO4H2O,0-5°C(CH3)2CHOH(73%)Example②2.KI,roomtemp.1.NaNO2,HClH2O,0-5°C(72-83%)NH2BrIBrExample③(68%)NH2CCH2CH3O2.HBF41.NaNO2,HCl,H2O,0-5°C3.heatFCCH2CH3OSchiemannreactionExample④(68-71%)NH2NO22.CuCl,heat1.NaNO2,HCl,H2O,0-5°CClNO2Sandmeyer

reactionsTraugottSandmeyer(1854-1922),wasborninWettingen,Switzerland,andreceivedhisPh.D.attheUniversityofHeidelberg.HespenthisprofessionalcareerdoingpharmaceuticalresearchattheGeigyCompany,Switzerland.Example⑤(89-95%)2.CuBr,heat1.NaNO2,HBr,H2O,0-10°CNH2ClBrClSandmeyer

reactionsSynthesizem-BromochlorobenzenenitrationchlorinationreductiondiazotizationSandmeyerreactionusethediazotizationandSandmeyerreactions.Example⑥(64-70%)2.CuCN,heat1.NaNO2,HCl,H2O,0°CNH2CH3CNCH3SandmeyerreactionExample⑦(70-75%)NaNO2,H2SO4,H3PO2NH2CH3CH3reductivedeaminationNH2BrBrBrExample⑧(74-77%)NaNO2,H2SO4,

H2O,CH3CH2OHNH2Br2H2O(100%)BrBrBrAnothervalueusageofDiazoniumSalts2.AzoCompound

DiazoniumsaltsreactwithstronglyactivatedaromaticcompoundsbyelectrophilicaromaticsubstitutionandgiveAzocompoundArNN+Ar'H+ArNNAr'anazocompoundAr'mustbearastronglyelectron-releasinggroup

suchasOH,OR,orNR2.ExampleOH+C6H5NN+OHNNC6H5Cl–

1.GabrielSynthesis

2.PreparationofAminesbyReduction

3.ReductiveAmination

4.LeuckartReaction

5.MannichReactionPreparationofAmines1.GabrielSynthesis

Gabrielsynthesisisthepreparationofpureprimaryaminemethod,firstinthestrongalkalineconditions,thephthalimidetransformintophthalimideanion,theanionandalkylhalidealkylation,andthenhydrolyzedtoobtainapureprimary

amine.ExampleOON•

••

•–K++C6H5CH2ClOONCH2C6H5•

•DMF(74%)GabrielSynthesisphthalimideanion+C6H5CH2NH2OONCH2C6H5•

•H2NNH2(97%)OONHNHPreparationofprimaryamineN-取代物在碱或酸中水解速度较慢、产率较低，现多用肼代替酸或碱进行肼解。thealcoholsulfonylacidesterisagoodreagent,

GabrielreactionisSN2nucleophilicsubstitutionreaction,iftheleavinggroupisconnectedwiththecarbonatomischiralcarbonatoms,theconfigurationwillbetransformed.SiegmundGabriel

(1851-1924)wasborninBerlin,Germany,andreceivedhisPh.D.in1874attheUniversityofBerlin,workingwith

AugustvonHofmann.Afterfurther

workwith

RobertBunsen,hebecameProfessorofChemistryattheUniversityofBerlin

SynthesisofAminesviaAzidesSN2reaction,followedbyreduct