第一節(jié)用硅對碳進行等電排置換設(shè)計更加安全的化學(xué)品

四川大學(xué)化學(xué)學(xué)院

Chapter4

Applicationof

DesigningSaferChemicals

4.1

IsostericReplacementofCarbonwithSilicon(用硅對碳進行等電排置換)intheDesignofSaferChemicals4.2DesigningBiodegradableChemicals

4.3DesigningAquaticallySaferChemicalsReferences4.1IsostericReplacementofCarbonwithSiliconintheDesignofSaferChemicals(用硅對碳進行等電排置換)SiliconisanIsostereofCarbonDifferencesbetweenSiliconcompoundsandCarboncompounds

ThedegradationandoxidativemetabolismoforganicsiliconcompoundsExamplesofisostericreplacementofcarbonwithsiliconforthedesignofsaferchemicals

四川大學(xué)化學(xué)學(xué)院4.1.1SiliconisanIsostericatomofCarbonCommonFeaturesofSiliconandCarbongroupedincolumn4AofthePeriodicTablehavingmanychemicalsimilarities

：

tetravalent,tetrahedral,andformstablebondswithcarbon.

金剛石碳化硅

SiliconisanIsostericatomofCarbonOrganicderivativesofsilicongenerallyhavenointrinsictoxicity,incontrastwiththeotherGroup4Aelementsgermanium(Ge),

tin(Sn),andlead(Pd).Fromatoxicityperspective,siliconistheonlyGroup4Aelementthatisasuitablereplacementforcarbon.Inaddition,siliconisanabundant,inexpensiveelementandonethatisavailableinavarietyofforms.四川大學(xué)化學(xué)學(xué)院Examples:

Urethanes(尿烷),naturalanalogsoftheneuro-transmitter(神經(jīng)傳遞質(zhì))acetylcholine(乙酰膽堿)(1),werefoundtobeantagonists(拮抗藥)of(1)withidenticaldose-responsecurves.

Interestingly,silane(silicon)wasmuchlesstoxictomicethanurethane(carbon),andexhibitedmusclerelaxantproperties.

Acetylcholine(乙酰膽堿)Urethane(尿烷)MuscarinicAntagonistis（蠅覃堿拮抗劑）Thetert-butyl(叔丁基)andtrimethylsilyl(三甲基硅)groupsfunctionsimplyasisosteresoftrimethylammonium(三甲基銨).CarbamateSiliconsubstitutedIsostereofcarbamate

(Moredegradable,lesstoxictohumanandenvironment)Carbamate(氨基甲酸酯)insecticideanditssiliconanalogwerefoundtohavesimilartoxicitytothehousefly.

Siliconistheelementmostsimilartocarbon,howeveritisnotagenericreplacementforallcarbonatomsandcertainstrictlimitationsapply.Doublebondstosilicon,andthree-memberedringscontainingsilicon,areunstabletoairandmoisture.

Singlebondsfromsilicontoheteroatomssuchasnitrogenandoxygenarestrongbutcanhydrolyzereadily.

4.1.2DifferencesbetweenSiliconandCarbonCompoundsAsubtleyetinfluentialdifferenceinatomicsizeexistsforsiliconandcarbon,importantdifferencesinchemicalreactivityalsoexist.Whensiliconisproximal(最接近的)tounsaturation,asinavinyl(乙烯基)orallyl(丙稀基)silane,thecompoundsarestable,butunliketheircarbonanalogs,theyaresubjecttoacidcatalyzedsilicon-carbonbondcleavage.

BreakingofC－Sibondiseasy.Hereinliesapotentialavenue(方法)forthedesignofenvironmentallydegradableproducts.

4.1.3ThedegradationandoxidativemetabolismoforganicsiliconcompoundAnimportantcomponentofdesigningsaferchemicalsispredictingtheirenvironmentfate,andbothabiotic(非生物)degradationandbiologicaloxidationcanplayarole.Designingchemicalsthatwillbiodegradetoinnocuousproductsishighlydesirable,andisostericsubstitutionofcarbonwithsiliconinmanycasesmayenhanceabioticdegradationandbiologicaloxidation.四川大學(xué)化學(xué)學(xué)院AbioticDegradationCurrentlythemajorenvironmentalsourceoforganosilaneissiliconepolymer(聚硅酮)(siloxanes硅氧烷),primarilypolymersof1,1-dimethylsilanediol.Siloxaneswereoncethoughttobeenvironmentallystable,butarenowknowntobedepolymerizedinthepresenceofwaterandsoil.Siliconepolymer(Siloxanes,聚硅酮)depolymerizeinthepresenceofwaterandsoil

tosilicatesfinallyExample1：SilaneAnalogsofDDTExample2：OrganosilaneFungicides(殺真菌劑)

4.1.4ExamplesfortheDesignofSaferChemicalsUsingSiliconSubstitutionforCarbon四川大學(xué)化學(xué)學(xué)院SilaneAnalogsofDDT

InanearlyefforttodesignamorebenignversionofDDT,anumberofsilaneanalogssuchastheDDDanalogwerepreparedwiththeanticipationthatthesewouldbelessenvironmentallypersistent.DDTSilaneAnalogsofDDT四川大學(xué)化學(xué)學(xué)院SilaneAnalogsofDDTThepresenceofthereadilyoxidizedsilicon-hydrogenbondwouldhavebeenonesourceofinstability,bothintheenvironmentandinvivo.Moresignificantforthisresearch,however,wasanSARstudythatfoundtheoverallsizeoftheDDTmoleculestronglycorrelatedwithbioactivity,implicatingtheatomicsizeofthecentralsiliconforthelackofinsecttoxicityforDDDandcongeners(同類).四川大學(xué)化學(xué)學(xué)院OrganosilaneFungicides

Asanovelentryintotheclassoftriazole(三唑)fungicides(殺真菌劑),Mebergandcoworkerspreparedaseriesofsilaneanalogs.Oneofthese,flusilazole(氟苯代硅三唑)provedtobeahighlyeffectivecrop

fungicide（谷類防真菌）andisnowamajorcommercialproduct.Flusilazole（氟苯代硅三唑）MetabolismUsage:crop

fungicide

四川大學(xué)化學(xué)學(xué)院

4.1IsostericReplacementofCarbonwithSilicon(用硅對碳進行等電排置換)intheDesignofSaferChemicals

4.2DesigningBiodegradableChemicals

4.3DesigningAquaticallySaferChemicalsReferences4.2DesigningBiodegradable

Chemicals四川大學(xué)化學(xué)學(xué)院Thesaferchemicaleliminates

theproductionandreleaseofmorepersistentandpotentiallyhazardoussubstitutesthrough

moleculardesign

toenhancebiodegradability

tonon-toxicproducts.

Enhancedbiodegradabilityisalsoaworthygoalpreciselybecausepollutioncannotalwaysbepreventedatthesource.ExamplesofDesigningBiodegradableChemicalsTheMicrobialBasisofBiodegradation

ChemicalStructureandBiodegradability

GroupContributionMethodforPredictingBiodegradability

四川大學(xué)化學(xué)學(xué)院Hazardscouldnotalwaysbeknownorpredicted：Chemicals:(resistbiodegradation)exerttoxiceffecttobiota(生物區(qū)),hardlytopredicttheirpotentialtoxiceffectatthetimeofreleasetotheenvironment.Moreover,bioaccumulativetoxicitycriteria(safe),butchronic(慢性的)orotherunforeseentoxiceffect(unknown).Increasingthesafetyofchemicals

IncreasingthetreatabilityofthewastegeneratedAnimals:

excrete

chemicalsthattheycannotmetabolize;

Plants:

tendto

convert

chemicalsintowaterinsoluble.

Microbialpopulations:

arecharacterizedby

catabolic(代謝分解的)versatility,

rapid

growthinthepresenceoffood,high

metabolicactivityandspeciesdiversity.

Theeventual

mineralization

oforganiccompounds(theirconversiontoinorganicsubstancessuchasCO2andwater)canbeattributed

predominantlytomicrobial

degradation.4.2.1TheMicrobialBasisofbiodegradation

Thekeyroleinbiodegradation:

Anabundanceof

evidenceexists

toshowthat

microorganismsareresponsiblefor

thedegradationofmanyorganicchemicalscannotbealteredsignificantlybyhigherorganism.

Microorganisms（primarilybacteria細菌andfungi真菌）arebyfarthe

mostimportant

agentsofbiodegradationinnature.四川大學(xué)化學(xué)學(xué)院Microbialdegradationisthemajorlossmechanismformostorganicchemicalsinaquatic(水的)andterrestrial（陸地）environments,andisthecornerstoneofthemodernwastewatertreatmentplant.成都活水公園SCU四川大學(xué)化學(xué)學(xué)院Theprocessofbiodegradation1.Anorganiccompoundmustfirstenterthemicrobialcellthroughthecellwall&cytoplasmic(細胞質(zhì))membrane.

Thismayoccurby

passivediffusion

orwiththeassistanceofspecifictransportsystems.

Especially:foraquaticandterrestrial(陸生的)environments——lowlevels

oforganicsubstrateandothernutrients.Forexample:

largepolymericsubstrates:proteins,polysaccharides(多糖),biodegradedtosmallerchemicalsbyextracellularenzymes(細胞外酶)

.Theprocessofbiodegradation2.Onceinsidethecell,thereactionsthatacompoundmayundergoaredeterminedbyitsmolecularstructure,hundredsoftransformationshavebeendescribedintheliterature,butalmostallcanbeclassifiedbroadlyas：

oxidative;reductive;hydrolytic;conjugativereactions

四川大學(xué)化學(xué)學(xué)院TheprocessofbiodegradationWhatprocessaspecialcompoundwillundergoinsidethecelldependsstronglyonitsmolecularstructure.

Inaddition,Thecatabolicpathwaysemployedbymicrobialpopulationsarealsodiverseandvarywiththeenvironmentalconditions.

Thestrategyofmicrobialdegradation

Butdespitetheimmensestructuralvarietyofnaturallyoccurringaswellasanthropogenic(人類引起的)compounds,theirutilizationbymicroorganismsalwaysinvolvesthesamebasicstrategy.Thatstrategyis

stepwisedegradation

toyieldoneormoreintermediateproductscapableofenteringthecentralpathwaysofmetabolism.Theoverallobjectiveisalwaystoproducecarbonandenergyforgrowth.四川大學(xué)化學(xué)學(xué)院Thestrategyofmicrobialdegradation

Persistentandtoxicintermediates

occasionallyarisefrompotentialbiodegradationofacompound,butthisistheexceptionratherthantherule.Naturallyoccurringorganiccompoundsaredegradableviapathwaysthatrepresentevolutionaryadaptationstoprevailingconditions.Gratuitousmetabolism（幸運代謝）

Manyman-madechemicalsareidenticalorsimilartonaturallyoccurringsubstances,buthumanactivitieshavealsoproducedstructuresneverseenoratleastinfrequentlyencounteredinnature.Manyofthese,nonetheless,canbeattackedbymicroorganismbyvirtueofaphenomenareferredtoas

GratuitousMetabolismorFortuitousMetabolism.Cause：degradativeenzymesgenerallyarenotabsolutelyspecificfortheirnaturalsubstances.四川大學(xué)化學(xué)學(xué)院ExamplesofDesigningBiodegradableChemicalsTheMicrobialBasisofBiodegradation

ChemicalStructureandBiodegradability

GroupContributionMethodforPredictingBiodegradability

4.2.2Relationshipbetweenchemicalstructureandbio-degradabilityThebio-degradabilityofasubstance,whichisoneofthepropertiesofthesubstance,dependsstronglyonitschemicalstructure.Studies,ResearchandEnvironmentalMonitoring:

Smallchangesinmolecularstructurecanappreciablyalterachemical'ssusceptibilitytobiodegradation!四川大學(xué)化學(xué)學(xué)院Relationshipbetweenchemicalstructureandbio-degradabilityThefollowingmolecularfeaturesgenerallyincreaseresistancetoaerobicbiodegradation:

Halogens;especiallychlorineandfluorine;Chainbranching（支鏈物質(zhì)）,especiallyquaternarycarbon（季碳）andtertiarynitrogen,orextensivebranchingsuchasinsurfactantsderivedfromtri-ortetrapropylene;Nitro,nitroso（亞硝基）,azo（偶氮基）,arylaminogroups（芳氨基）;Polycyclicresidues（多環(huán)殘基）(suchasinpolycyclicaromatichydrocarbons（多環(huán)芳香烴）orPAHs（稠環(huán)芳烴）),especiallywithmorethan3fusedrings;Heterocyclicresidues（雜環(huán)殘基）;e.g.,pyridinerings（吡啶環(huán)）;Aliphaticether(C-O-C)bonds（脂肪族醚鍵）.High-substitutedcompounds.Relationshipbetweenchemicalstructureandbio-degradabilityTheCauseforresistancetobiodegradability

Forthemostpart,thefeatureslistedaboveaffecttheabilityofthecompoundtoserveasaninducerorsubstrate,orboth,ofdegradativeenzymesandcellulartransportsystems.

Forexample,Additionofachlorineatomtoaphenylringmakestheringlesssusceptibletoattackbyoxygenaseenzymes,whichutilizeaformofelectrophilicoxygenasacosubstrate(共存底物).Stronglyelectron-withdrawing(吸電子)substituentssuchashalogensarethereforetobeavoidedinchemicaldesignifpossible.

四川大學(xué)化學(xué)學(xué)院Note:Thislistisnotexhaustive(詳盡的),norshoulditbeinferredthatthepresenceofevenasingleatomorgroupfromthelistnecessarilyrendersacompoundrecalcitrant(反抗的).Moreover,inmostcasesthemechanismbywhichincreasedresistancetobiodegradationisconferredisnotknownindetail.Butthisshouldnotblindustothefactthatsufficientinformationisavailabletoallowapplicationoftheseprinciplesinchemicaldesign.ThechemicalstructureswhichfavorbiodegradabilityBiodegradabilityisusuallyenhanced:

bythepresenceofpotentialsitesofenzymatichydrolysis(e.g.,esters,amides);bytheintroductionofoxygenintheformofhydroxyl(羥基),aldehydic(醛基)orcarboxylic(羧基)groups;bythepresenceofun-substitutedlinearalkylchains(especially>4carbons)andphenylrings,whichrepresentpossiblesitesforattackbyoxygenases.Thefirststepofbiodegradationissomekindofoxidationreaction.Andthisstepisalmostalwaysratelimiting.Thesecondofthesethreefactorsisparticularlyimportantbecausethefirststepinthebiodegradationofmanycompounds(e.g.,hydrocarbons)istheenzymaticinsertionofoxygenintothestructure.ThechemicalstructureswhichfavorbiodegradabilityTheimportanceofinsertingoxygeninthe

moleculeMoregenerally,ifthefirstbiodegradativestepissomeformofoxidation,itseemslogicaltoexpectthatbiodegrabilitywillbeenhancedifthesyntheticchemisthasineffectalreadycarriedit(oxygeninserted)outduringmoleculardesign.Thesolubilityandbio-degradabilityTheaqueoussolubilityofthemoleculesaltersignificantlythebiodegradability.

Thepossibleeffectsofsolubilityonbiodegradabilityareasthefollowing：1:Microbialbioavailability(微生物生物利用度)

Insolublechemicalstendtoadsorbinactivatedsludge(淤泥),sediments(沉積物)andsoil(土壤).

Moststudieshaveshownthatthistendstoreducetherateofbiodegradation.

Underthesameconditions,theinclusionofgroupswhichincreasethesolubilityofainsolublechemicalmayincreaseitsbiodegradability.Thesolubilityandbio-degradabilityThesolubilityandbio-degradability2：Rateofsolubilization(溶解速度)Moststudieshaveshownthatforsolidwithverylowsolubility,onlythedissolvedordispersedphaseisavailabletomicroorganisms.Therefore,therateofdissolutionofasolidinwatermaycontroltherateofbiodegradation.Manymicroorganismsexcretebiosurfactants(e.g.,rhamnolipids,鼠李糖脂)thatenhancetherateofsolubilizition.

Thesolubilityandbio-degradability

3：Lowaqueousconcentration

Somestudieshaveshownthatforchemicalssolubletotheextentofonlyafewmicrogramsperliterorless,thisconcentrationmaybetoolowforoptimalfunction(無法發(fā)揮其最佳功能)ofcellularenzymes(細胞酶)ortransportsystems(傳輸系統(tǒng)).Thusthebiodegradabilityislimited.四川大學(xué)化學(xué)學(xué)院Thesolubilityandbio-degradabilityAtthepresentitcanbestatedthat:(i)highlysubstitutedstructuresarelikelytobelessrapidlybiodegradedthanmuchsimplercompounds;and(ii)forveryinsolublechemicals,replacementofagivenfunctionalgroupwithonethatincreasessolubilitymayalsoresultinenhancedbiodegradability.四川大學(xué)化學(xué)學(xué)院ExamplesofDesigningBiodegradableChemicalsTheMicrobialBasisofBiodegradation

ChemicalStructureandBiodegradability

GroupContributionMethodforPredictingBiodegradability

4.2.4ExamplesofDesigningBiologicallySaferChemicalsLinearAlkylbenzeneSulfonates(線性烷基苯磺酸,LAS）DialkylQuaternaries(二烷基季銨)AlkylphenolEthoxylates(烷基酚乙氧基化物,APES）

1:LinearAlkylbenzeneSulfonates

（線性烷基苯磺酸鹽,LAS）

1884:Lever&CostartsproducingSunlightsoap.

1900:SunlightFlakesbecameLuxFlakes(力士皂片).

1930:Lever&Co-Unilever(聯(lián)合利華)1940s:ABS.Atfirstthealkylchainswerederivedfromakerosene(煤油)fractionoranimalfats.四川大學(xué)化學(xué)學(xué)院LinearAlkylbenzeneSulfonatesTheseproductsweresoonreplacedbyABS(烷基苯璜鹽)producedfrompropylenetetramer(四聚丙稀).

Tetrapropylenealkylbenzenesulfonate(TPBS,四丙基苯璜酸鹽)moreefficaciousandeconomical.四川大學(xué)化學(xué)學(xué)院LinearAlkylbenzeneSulfonatesWhatwillhappenwithhighlybranchedhydrocarbons

???Tetrapropylenealkylbenzenesulfonate(TPBS)四川大學(xué)化學(xué)學(xué)院Environmentalproblem

TPBS(四丙基苯璜酸鹽):Highlybranchedproductsincompletelybiodegradedinmunicipalsewage(城市污水)treatmentsystems.TPBSwasdegradedbyonlyabout50%insewagetreatmentunitsandasaresultexcessivefoamingoccurredinactivatedsludgeaeration(通風(fēng))tanks,aswellasinreceivingrivers.四川大學(xué)化學(xué)學(xué)院Howtosolvethisproblem???Thefoamingwasfarworsethanthatcausedbyproteinaceous(蛋白質(zhì)的)materialinsewagepriortotheintroductionofsyntheticsurfactantsandinextremecasessewage-worksoperatorswerekilledbyasphyxiation(窒息)afterfallingintofoamingtanksfromwalkwaysmadeslipperybythefoam...Becauseofitsincompletebiodegradation,theconcentrationofTPBSinriverwaterswasashighas2mgL-1,andwatertendedtofoamwhencomingoutofthetap."UsinglinearAlkylbenzeneSulfonates(LAS)toreplaceTPBS:thestructureEventuallymethodsweredevelopedthatpermittedtheeconomicalmanufactureofamoreenvironmentallyacceptableproduct

LAS,LASsurfactantscouldbecompletelydegradatedinmunicipalsewagetreatmentsystems.四川大學(xué)化學(xué)學(xué)院

4.1IsostericReplacementofCarbonwithSilicon(用硅對碳進行等電排置換)intheDesignofSaferChemicals4.2DesigningBiodegradableChemicals

4.3DesigningAquaticallySaferChemicalsReferences4.3

DesigningAquaticallySaferChemicals

四川大學(xué)化學(xué)學(xué)院Aquaticspecieshavetheirownuniquerolesinecosystemsandareimportantforthesubsistenceofotherspecies,includingconsumerandpredator(捕食者).

Amongotherthings,aquaticspeciescomprisethecomponentsoffoodchainsthatleadtoman.

ToxiceffectsofChemicalstoAquaticspeciesGreenalgae(綠藻)aretheprimaryproducersinaquaticecosystemsinthat,throughphotosynthesis,theyproduceoxygenandsynthesizecarbohydratesandotherfoodstuffs.ToxiceffectsofChemicalstoAquaticspecies四川大學(xué)化學(xué)學(xué)院

Thesurvivalofterrestrialspecies,includinghumans,isatleastpartiallydependentuponaquaticorganisms.Chemicalsthataretoxictoaquaticspeciesmaythereforeputanecosystematunreasonableriskofharm,andcanleadtodisruptionofsomefoodchains.ToxiceffectsofChemicalstoAquaticspecies四川大學(xué)化學(xué)學(xué)院ToxiceffectsofChemicalstoAquaticspeciesTherearetwogeneraltypesofchemical-inducedlethality(致命性，毀壞性)inaquaticorganisms:

non-specific(i.e.,narcosis)；

specific.Themajorityofchemicalsthataretoxictoaquaticspeciesaretoxicbynarcosis（麻醉）.NarcosisToxicityThemechanisticbasisofnarcosistoxicity(麻醉致毒)：

Achemicaldiffusesacrossthebiologicalmembranesofanaquaticorganism(e.g.,gillsinfish).Onceahighenoughconcentrationisreachedwithinthecellsorincellularmembranes,itwillcausenon-specificperturbationsincellularfunction.Theseperturbationscanleadtodeathifasufficientconcentrationofachemicalhasdiffusedintooracrosscellularmembranes.

四川大學(xué)化學(xué)學(xué)院Chemicalswithonlyanarcoticmodeoftoxicactionarethosethatdonotreactwithcellularmacromolecules,andrepresentavarietyofchemicalclassesincludingchlorinatedhydrocarbons,alcohols,ethers,ketones,weakorganicacidsandbases,andsimplearomaticnitro-compounds,tonamejustafew.NarcosisToxicityNarcosisToxicity

Becausecellularmembraneshaveahigherlipidcontent,theyaremorereadilypenetratedbynon-polar,lipid-solublechemicalsthanbylipid-insolublepolarchemicals.Thus,therelativetoxicpotencyofanon-polarsubstancethatactsthroughanarcosismechanismisafunctionofitslipophilicity.Narcosis,inprinciple,correspondsmechanisticallytothesamenon-specificmodeofaction,inducedbygaseousanestheticdrugs.Narcosistoxicityrepresentsbaselineorminimumtoxicity.

SpecificorReactivetoxicity

Incontrasttochemicalsthatareonlytoxicbynarcosis,somechemicalsaretoxictoaquaticorganismsasaresultofachemicalreactionoraspecificinteractionbetweenthechemical(oritsmetabolite)withacriticalcellularmacromolecule.Thechemicalsexhibitexcesstoxicitytothatofnarcosisandisnamedspecificorreactivetoxicity.

四川大學(xué)化學(xué)學(xué)院SpecificorReactivetoxicity

Forexample,excesstoxicitycanbeexpectedtoresultifachemical(oritsmetabolite)cancovalentlybondtocriticalproteinmolecules(e.g.,enzymes,DNA)orinteractcovalentlywithcellularreceptorsites.

Examplesofthetypesofchemicalsthatmayexhibitexcess(specific-type)toxicitytoaquaticorganismsarecyanogens(氰),electrophiles(e.g.,alkylatingagents),andchemicalsmetabolizedtoelectrophilicchemicals.1.UseofStructure-ActivityRelationshipstoPredictAquaticToxicity

2.ModificationofPhysicochemicalPropertiesandStructure

3.ModificationofChemicalStructureviaChemicalClass

4.3.1UseofStructure-ActivityRelationshipstoPredictAquaticToxicity四川大學(xué)化學(xué)學(xué)院WhatisSARs???

SARsrefertotheabilityofagroupofanalogouschemicalstoproduceaparticularbiologicaleffect,andtheinfluencethatthestructuraldifferencesbetweenthechemicalshaveonrelativepotencyinproducingthebiologicaleffect.QSAR（定量構(gòu)效關(guān)系）：

physicochemistrypropertiesIn1976,theUnitedStatesCongresspassedtheToxicSubstancesControlAct(TSCA,毒物控制提案).OneofthemajorobjectivesofTSCAistocharacterizeandunderstandtherisksanewchemicalposestohumansandtheenvironmentbefore

thechemicalisintroducedintocommerce,sothatsuchriskcanbeminimizedorprevented.UseofStructure-ActivityRelationshipstoPredictAquaticToxicity四川大學(xué)化學(xué)學(xué)院Inordertoidentifyrisksposedbynewchemicalsforwhichnodataareavailable,andtodosounderthestricttimeconstraintsprescribedbyTSCA,theEPAbasesmanyofitstoxicityassessmentsonstructure-activityrelationships(SARs).QSAR（定量構(gòu)效關(guān)系）-physicochemistryproperties：octanol-waterpartitioncoefficient(logPorlogKow),watersolubility,dissolutionconstant,relativemolecularweight,etc.UseofStructure-ActivityRelationshipstoPredictAquaticToxicity4.3.2AdjustingtheStructureandPhysicalChemicalProperties

四川大學(xué)化學(xué)學(xué)院RelatedPhysicalChemicalProperties(1)Octanol-WaterPartitionCoefficient

（logP或logKow）(2)WaterSolubility(3)MolecularSizeandWeight(4)IonPair(5)Zwitterions(兩性離子)(6)Chelation

(螯合作用)(1)Octanol-WaterPartitionCoefficient

（logP或logKow）Theoctanol-waterPartitionCoefficientisatermusedtoexpressasubstance'slipophilicity.Itisthephsicochemistrypropertymostfrequentlyusedtoestimatetheaquatictoxicityoforganicchemicals.ThisisbecauselogPoftencorrelateswellwithbiologicalactivity.

logPwaterOctanol

ForNonionicOrganicSubstancethatonlyexhibitanarcoticmodeoftoxicaction：

logP≤5，

itsacutetoxicityandchronictoxicitywillincreaseexponentiallywithincreasinglipophilicity(notfordyes,polymers,andsurfacts)；

logP＞5，toxicityfollowingacuteexposuredecreasesexponentially

logP:5-8，onlychronictoxicity

logP:≥8，notoxicity

Octanol-WaterPartitionCoefficient

四川大學(xué)化學(xué)學(xué)院"Narcotic"chemicalssuchasaliphaticalcohols,chlorinatedbenzenes,ketenes,disulfides,and"reactive"chemicalssuchasacrylates(丙烯酸鹽),estersacuteaquatictoxicityuptologPof6.

However,somereactivechemicals,suchas,aliphaticamines(脂肪胺)surfactantslogPvaluesgreaterthan8maystillexhibitacutetoxicity.

Octanol-WaterPartitionCoefficient

Ontheotherhand,

chemicalswithlowlogPvaluesarenotsufficientlylipophilictoenterthecellularmembranesofaquaticorganisms,andtherefore,arenotbioavailableandareoflowtoxicity.Forexample,chemicalswithmolecularweightsoflessthan200daltonsandhavealogPof2orlowerhavelowtoxicitytoaquaticspecies,i.e.,acutemedianlethalconcentration(LC50)valuesgreaterthan100mg/L.Octanol-WaterPartitionCoefficient

Forchemicalswhoseaquatictoxicityisduetonarcosis,chronicandacuteaquatictoxicityChemistscanreducethepotentialforaquatictoxicitybydesigningchemicals.molecularweightsoflessthan200daltons,logP<2,logP>8regardlessofmolecularweight.

TodecreaselogP,polarsubstitutessuchascarboxylic,alcoholic,orotherwatersolublegroupscanbeaddedtochemicals,andtheresultantlogPofthemodifiedsubstancecanbecalculated.Ontheotherhand,logPcanbeincreasedbyaddinghydrophobicgroupssuchashalogens(鹵素),phenylrings,andalkylgroups.(2)WaterSolubility

Asageneralrule,chemicalshavingwatersolubilitylessthan1ppbareessentiallynon-toxictoaquaticspeciesduetolowbioavailability.

Forexample,tertiaryamylalcohol(叔戊醇)is98g/Lmorewatersolublethanitsisomern-pentanol(正戊醇).CH3CH2C(OH)(CH3)2

CH3CH2CH2CH2CH2OH

a＋98g/L

ag/L

(3)MolecularSizeandWeight

Ifthenewchemical'smolecularweightisincreased,thechemicalwillbelesstoxictoaquaticorganismswhileholdingallotherfactorsconstant.Atamolecularweightof1000Daltons,uptakewillbenegligiblebecausethechemicalwillnotdiffuseacrosstherespiratorymembranesofaquaticorganisms.Chemicalswithminimumcross-sectiondiametersgreaterthan1nmaretoolargeforpassivediffusionanduptakethroughtherespiratorymembranesofaquaticorganisms.

Naturalphthalocyaninedyes(天然酞菁染料)

minimumcross-sectionaldiameters>>1nm.lowacuteandchronictoxicitytoaquaticorganismsTheDesignPrinciple*toincreaseminimumcross-sectionaldiameters*toincreasethemoleculesize（4）IonPair

Somechemicalsaltsexistasstrongionpairswhenanionanditscounterionareassociatedstronglywithoneanother.Thesechemicalsdissociateweaklyornotatallinwater,consequently,mayhavelowwatersolubilityandlowaquatictoxicity.Ifasolubleandchargedchemicalcanbeconvertedtoastrongionpairandstillretainitsusefulne