華科分析藥理課件-有機化學chapter14含氮

AminesCompoundscontainingNitrogenatom本章內容；1、硝基化合物(nitrocompounds)2、胺(amines)3、季銨鹽和季銨堿(Quaternary

Saltsand

QuaternaryAmmoniumHydroxides)4、重氮化合物與偶氮化合物

(diazoandazocompounds)第一節(jié)、硝基化合物硝基化合物(nitrocompounds)是指烴分子中的氫原子被硝基(－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硝基化合物亞硝酸酯Structure127O122pm122pm硝基中，氮原子為sp2雜化氮原子上未雜化的p軌道和兩個氧原子上的p軌道互相重疊，形成包括三個原子在內三中心四電子的大π鍵分子軌道：Nomenclature與鹵烴相類似，以烴為母體，硝基作為取代基。例如：

nitroethane

2-nitropropane

4-nitrotoluene2,4,6-trinitrotoluene

Chenmicaireaction1.有關硝基對α-H影響的反應(1)酸性Why?Goodnucleophilicreagent硝基式假酸式酸性和互變異構具有α氫的硝基化合物與強堿作用生成鹽：含α氫的1°和2°脂肪族硝基化合物能逐漸溶于強堿的水溶液中并形成鹽，表現(xiàn)出明顯的酸性。一般認為這是由于這些硝基化合物中存在著下列互變異構現(xiàn)象：(2)縮合反應2.硝基對鄰、對位取代基活性的影響

加成消除機理使甲基的氫易離去3.硝基的還原在堿性介質中發(fā)生雙分子還原在中性介質中生成苯基羥胺選擇性還原Impossibletopredictwhichnitrogroupwillbereduced

AminesAminesareusedin…殺蟲劑Pesticide染料Dye制藥Manufacturesdrugs聚合物PolymerAminesare…氨的衍生物(NH3).它既是堿又是酸第二節(jié)、胺類SomeExamplescocaine

3°aminestreucturecocainecocaine

plantcocaine

flower

苯丙胺類興奮劑均具有中樞神經(jīng)系統(tǒng)興奮作用，但不同藥物的作用各有側重amphetamine

NicotineCaffeineProcaine胺是氨的衍生物ammoniaamine

derivatives1o2o3oPrimaryamineSecondaryamineTertiaryaminequaternary

salt1.Classification:可為aliphatic,aromatic,andhetero-cyclicamines:aliphaticamines:氮直接連接在脂基上aromaticamines:氮直接連接在芳基上heterocyclicamines:氮在環(huán)中2.Nomenclaturemethylamine

ethylamine

cyclohexylaminetert-butylamine1).Primaryamines(RNH2)arenamedbyaddingtheword“amine”tothenameoftheRgroup.PrimaryaminescanbenamedinIUPACsystemintwoways2).analogoustoalcohols:replace-eendingby-amineCH3CH2NH2ethanamineNH2cyclohexanamineCH3CHCH2CH2CH3NH22-pentanamine3)NomenclatureofPrimaryArylamines(ArNH2)NameasderivativesofanilineNH2只有當氨基直接連接在芳環(huán)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甲胺的結構

胺具有棱錐形的結構.Theaminestructureandtheammoniaaresimilar.

nitrogenatomissp3hybridization,

theamineasthetetrahedralstructure,nitrogenatomseemstobeaschiralatoms.simpleamineenantiomersresolutiondidnotsucceed.氨、甲胺和三甲胺的結構如下：Aromaticaminesarealsosp3hybridization，nitrogenatombondedwiththecarbonatomsofsp2

hybridcarbon，alsomakesthenitrogenatomasthecenterofthetetrahedron,thealiphaticaminesareintheflatshape，porbitalofthenitrogenconjugatedwiththebenzenering.Structureofaniline

INVERSIONOFSMALLAMINESIffastinversionoccurs,apyrimidalnitrogenwillnotbeanactivestereocenter.RACEMICMIXTUREOFENANTIOMERS手性季銨鹽正離子，可以被拆開成對映體。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;在對位比在間位更為明顯。③Forthetwoeffectsofonegroups,itsimpactdependsontwokindofeffectthedirectionandrelativestrength.

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

PhNH2pKa4.003.48

芳香胺的堿性比氨和脂胺弱得多，這是因為氮上未共用電子對與苯環(huán)有共軛作用，分散了氮上的這一對電子，使其堿性大大減弱。在芳胺中，氮上的氫原子若被烷基取代，會使堿性增強。如：PhN(CH3)2>PhNHCH3>PhNH2芳胺和脂胺的堿性比較芳脂胺的堿性大于芳胺。季銨堿因在水中可完全電離,因此是強堿,其堿性與氫氧化鉀相當。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

?；酋；痯rimaryandsecondaryaminescanalsoreactwithacidchloridestoformsubstitutedamides.Buttertiaryaminesfailtoyieldamides.

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

PrimaryArylamines

withNitrousAcidStructureofarenediazoniumsaltsReactionsMechanismofPrimaryArylamineswithNitrousAcidReactionsofPrimaryAliphaticAmineswithNitrousAcid定量放出氮氣測定－NH2的量混合物無制備價值Ring-expansionreaction；可用于制備五至九元的環(huán)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硫酸氨基是間位定位基乙酰氨基是鄰對位定位基②.HalogenationofArylamines反應定量完成，可用作定性、定量分析。③.Friedel-CraftsReactionsTheaminogroupofanarylaminemustbeprotectedasanamidewhencarryingoutaFriedel-Craftsreaction.NHCCH3OCH2CH3CH3CClOAlCl3(57%)NHCCH3OCCH3OCH2CH3④.Sulfonationreaction

rearrangment磺胺類藥物母體磺化氯磺化

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制備；芳香族伯胺與亞硝酸在低溫下反應，生成重氮鹽。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-取代物在堿或酸中水解速度較慢、產(chǎn)率較低，現(xiàn)多用肼代替酸或堿進行肼解。thealcoholsulfonylacidesterisagoodreagent,

GabrielreactionisSN2nucleophilicsubstitutionreaction,iftheleavinggroupisconnectedwiththecarbonatomischiralcarbonatoms,theconfigurationwillbetransformed.SiegmundGabriel

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

AugustvonHofmann.Afterfurther

workwith

RobertBunsen,hebecameProfessorofChemistryattheUniversityofBerlin

SynthesisofAminesviaAzidesSN2reaction,followedbyreduct