anchoring concepts workshop - beyond benign
TRANSCRIPT
AnchoringConcepts:Linkingchemistryconceptstotoxicologytopicswithinintroductorychemistrycourses
AmyS.Cannon,Ph.D.ExecutiveDirectorBeyondBenign
2017GreenChemistry&EngineeringConferenceToxicologyforChemistsWorkshop
BeyondBenign’smissionistoequipeducators,scientists,andcitizenswiththetoolstoteachandpracticegreenchemistrytoachieveasustainablesociety.
Weenvision aworldwherescientistsandcitizensentertheworkforcewiththeskillstodesignandchoosegreener,sustainabletechnologiesthatspurtheinnovationeconomy.
BeyondBenign:MissionandVision
BeyondBenign:K–20Programs
ProfessionalDevelopmentforeducatorsongreenchemistry,toxicologyandsustainablescience
GreenChemistryCurriculumthatreplacestraditionalhazardouschemicalsinthelabandarebasedonreal-worldgreentechnologicalinnovations
CommunityEngagementthroughgreenchemistryandsustainablesciencehands-onactivities
LeadTeacherProgramthatprovidesK-12scienceeducatorswithanopportunitytobecomegreenchemistryteacherleaders
ACollegeStudentFellowsProgramtofostergreenchemistryandleadershipskillsforcollegestudents
The GreenChemistryCommitmentforhighereducationinstitutions tointegrategreenchemistryacrossthesub-disciplinesofchemistry
ToxicologyforChemistsCurriculumthatprovidesthenextgenerationofscientistswiththeskillstocreateproductsthataresafeforhumansandtheenvironment.
GreenChemistryStudentLearningObjectivesSigninginstitutionsagreethatupongraduation,allchemistrymajorsshouldhaveproficiencyinthefollowingessentialgreenchemistrycompetencies:• Theory: HaveaworkingknowledgeofthetwelveprinciplesofGreenChemistry• Toxicology:Haveanunderstandingoftheprinciplesoftoxicology,themolecularmechanismsofhowchemicalsaffecthumanhealthandtheenvironment,andtheresourcestoidentifyandassessmolecularhazards
• LaboratorySkills:Possesstheabilitytoassesschemicalproductsandprocessesanddesigngreeneralternativeswhenappropriate
• Application:Bepreparedtoservesocietyintheirprofessionalcapacityasscientistsandprofessionalsthroughthearticulation,evaluationandemploymentofmethodsandchemicalsthatarebenignforhumanhealthandtheenvironment
GreenChemistryCommitment
www.greenchemistrycommitment.org
1.Prevention. Itisbettertopreventwastethantotreatorcleanupwasteafteritisformed.
2.AtomEconomy. Syntheticmethodsshouldbedesignedtomaximizetheincorporationofallmaterialsusedintheprocessintothefinalproduct.
3.LessHazardousChemicalSynthesis.Wheneverpracticable,syntheticmethodologiesshouldbedesignedtouseandgeneratesubstancesthatpossesslittleornotoxicitytohumanhealthandtheenvironment.
4.DesigningSaferChemicals.Chemicalproductsshouldbedesignedtopreserveefficacyofthefunctionwhilereducingtoxicity.
5.SaferSolventsandAuxiliaries.Theuseofauxiliarysubstances(solvents,separationagents,etc.)shouldbemadeunnecessarywheneverpossibleand,whenused,innocuous.
6.DesignforEnergyEfficiency.Energyrequirementsshouldberecognizedfortheirenvironmentalandeconomicimpactsandshouldbeminimized.Syntheticmethodsshouldbeconductedatambienttemperatureandpressure.
7.UseofRenewableFeedstocks.Arawmaterialorfeedstockshouldberenewableratherthandepletingwhenevertechnicallyandeconomicallypractical.
8.ReduceDerivatives.Unnecessaryderivatization(blockinggroup,protection/deprotection,temporarymodificationofphysical/chemicalprocesses)shouldbeavoidedwheneverpossible .
9.Catalysis.Catalyticreagents(asselectiveaspossible)aresuperiortostoichiometricreagents.
10.DesignforDegradation.Chemicalproductsshouldbedesignedsothatattheendoftheirfunctiontheydonotpersistintheenvironmentandinsteadbreakdownintoinnocuousdegradationproducts.
11.Real-timeAnalysisforPollutionPrevention.Analyticalmethodologiesneedtobefurtherdevelopedtoallowforreal-timein-processmonitoringandcontrolpriortotheformationofhazardoussubstances.
12.InherentlySaferChemistryforAccidentPrevention.Substanceandtheformofasubstanceusedinachemicalprocessshouldbechosensoastominimizethepotentialforchemicalaccidents,includingreleases,explosions,andfires.
The Twelve Principles of Green Chemistry
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9PhDgrantinginstitutions– UniversityofCalifornia,Berkeley(2014,
#1,USNews&WorldReport)– UniversityofCalifornia,Davis(2014,
#32,USNews&WorldReport)– UniversityofMinnesota(2014,#24,US
News&WorldReport)– NortheasternUniversity(2014,#92,US
News&WorldReport)– SouthDakotaStateUniversity– MichiganTech– UniversityofToledo– UniversityofToronto(FirstinCanada!)– DrexelUniversity
2MSgrantinginstitutions– MontclairState– SUNYFredonia
25BAorBSgrantinginstitutions4CommunityColleges
4MethodsofImplementingToxicology
• IndependentCourse• Student-LedCourse• SeminarSeries• IntegratingintoExistingChemistryCourse
ToxicologyWorkingGroup
• Addressingtheknowledgegapoftoxicologyandunderstandingmolecularhazardsinthechemistrycurriculum
• ComprisedofGreenChemistryCommitmentsigners&outsidestakeholders• Collaboratewithindustryexperts• OrganizeSymposiaandWorkshops
• GreenChemistry&EngineeringConference,June13-15,2017• SocietyofToxicologyConference,2018• BCCE,2018
ToxicologyWorkingGroup
Today’sdiscussion1. ReviewAnchoringConceptMap:OrganicChemistry2. Introducecasestudies
• RelationshipBetweenpKa andSkinIrritation• DesignforBiodegradability
• ElectrophilicAromaticSubstitution• Alkanes:nomenclatureandisomers
• Bondstrengthandpersistence• Chirality• Electrophilic-NucleophilicReactions
AmericanChemicalSocietyAnchoringConceptMaps
I. Atoms:Matterconsistsofatomsthathaveinternalstructuresthatdictatetheirchemicalandphysicalbehavior.A. Atomshaveuniquechemicalidentitiesbasedonthe
numberofprotonsinthenucleus1. Theatomicnumberandmassnumberareusedto
determineaverageatomicweightandidentifyisotopes,whichplayapartinunderstandingtechniquessuchasMS,orNMR,orIRandratesofreactionsviakineticisotopeeffects.a. StabilizationofanionshelpstoexplainpKa
valuesandrelativeaciditiesofprotons.
Today’sdiscussion1. ReviewAnchoringConceptMap:OrganicChemistry2. Introducecasestudies
• RelationshipBetweenpKa andSkinIrritation• DesignforBiodegradability
• ElectrophilicAromaticSubstitution• Alkanes:nomenclatureandisomers
• Bondstrengthandpersistence• Chirality• Electrophilic-NucleophilicReactions
RelationshipBetweenpKa andSkinIrritation
Figure 1: Layers of the human skin with Erythema skin irritation location.
pKa valuescanassistinpredictingcompoundtoxicokinetic behaviorfor:
• SkinIrritation• Gastrointestinalabsorption• Membranepermeability• Proteinbinding• Metabolictransformations
pKa asanindicatorofskinirritation:pKa >8andpKa < 4
RelationshipBetweenpKa andSkinIrritation
1. Researchthefollowingstructures:• Imipramine• Nicotine• Norephedrine• 8-Aminoquinoline• Benzimidazole
2. IdentifytheirpKa value(literature)
3. IdentifythemostacidicH
4. Predictwhetherornottheywillbeskinirritants
5. LookattheSDStoseeifthereisanyreportedevidenceofskinirritation
RelationshipBetweenpKa andSkinIrritation
1. Researchthefollowingstructures:• Imipramine• Nicotine• Norephedrine• 8-Aminoquinoline• Benzimidazole
2. IdentifytheirpKa value(literature)
3. IdentifythemostacidicH
4. Predictwhetherornottheywillbeskinirritants
5. LookattheSDStoseeifthereisanyreportedevidenceofskinirritation
3.8
5.48
9.5 7.84
9.0
RelationshipBetweenpKa andSkinIrritation
Context:Nicotinepatch;dermaldrugdelivery
Nicotinecasestudy:• LD50(70mg/kg(rat,oral))• Nicotinetoxicity• Understandingdoseandexposuremechanisms• Toxicokinetics andToxicodynamics
DesignforBiodegradability
ØAppropriatemicroorganismsdonotexistorarenotpresentintheenvironment
ØThereareinadequatenutrientsforthemicrobialpopulationØThetemperature,pHorpO2 istoolowortoohigh;ionicconditionsareunsuitableØConcentrationofsubstrateistoohigh(toxic)ortoolowØThesubstrateisadsorbedorcovalentlyattachedtoclays,humus,etc.,orisphysicallyinaccessible
ØThesubstrateisnotaccessibletoattackbecauseitistoolargeand/orinsoluble
ØThesubstrate:Ø IsnottransportedintothecellØ IsnotasubstratefortheavailableenzymesØ IsnotaninducerforappropriateenzymesortransportsystemsØ DoesnotgiverisetoproductsthatcanintegrateintonormalmetabolismØ Isconvertedintoproductsthataretoxicorinterferewithnormalmetabolism
Chem.Reviews,2007,Vol.107,No.6,2207-2227
Environment
Molecule
Feature StructureHalogens: Especially chlorine and fluorine and if more than 3 in a moleculeChain branching if extensive: Quaternary C’s are problematic
Tertiary amine, nitro, nitroso, azo, and arylamino groups
Polycyclic aromatic residues
Heterocyclic residues
Aliphatic ether bonds (except in ethoxylates)
Featuresthatincreaseresistancetoaerobicbiodegradation:
DesignforBiodegradability
Feature StructureGroups susceptible to enzymatic hydrolysis (esters, including phosphate esters) and amides
Oxygen atoms in the form of hydroxyl, aldehyde, or carboxylic acid groups, ketones (not ether, with the exception of ethoxylategroups)Unsubstituted linear alkyl chains (especially ³ 4 carbons) and phenyl rings
Molecularfeaturesthatgenerallyincreaseaerobicbiodegradability:
DesignforBiodegradability
DesignforBiodegradabilityAlkylbenzene Sulfonates:
• Becamethestandardforhouseholdlaundryproductsinthe1940’s• Tetrapropylene alkylbenzene sulfonate (TPBS)wasderivedfromapetroleumfractionandeasy&economicaltomake
• TPBSdegradedonly~50%insewageplants,resultinginexcessivefoaming(alsoinrivers)
• Conc.ofTPBSinriverwaterswashigh(2mg/L)andwaterwouldfoamwhencomingoutofthetap
• Linearalkylbenzene sulfonate (LAS)replacedTPBSbytheearly1960’s• LASisalmostcompletelybiodegradableinsewagetreatment(morethan98%)
• Publicpressure/policy:TPBSwascheapertomake,butpublicpressurechangedtheeconomics
TPBS LASCheer:https://www.youtube.com/watch?v=lMxlAIeI8QIDash:https://www.youtube.com/watch?v=F1YTHr4mTQA
DesignforBiodegradability
Organic Chemistry Concepts:• Naming of alkyl chains• Understanding and identifying isomers• Condensed and bond-line formula• Identifying functional groups
Toxicology Concepts:• Persistence/Biodegradability• Half-life
DesignforBiodegradability
Organic Chemistry Concepts:• Electrophilic aromatic substitution
(electrophilic addition where oxygen is added to a phenyl ring)
• Substituent effects
Toxicology Concepts:• Persistence/Biodegradability• Half-life
OH OH
Cl
OHCl
ClCl
Cl
ClOH
ClCl
ClOH
Cl Cl
Clphenolpesticide
disinfectant"Dowicide 2S"
fungicide antiseptic
"Dowicide 2"pesticide
synthetic intermediate in
the preparation of dyes and drugs
BondStrength
Organic Chemistry Concepts:• Bond strength• Bond length
Toxicology Concepts:• Persistence• Structure and function
Carbon-Fluorine
Carbon-Chlorine
Carbon-Bromine
Carbon-Iodine
Structure
C-XBondLength
C-XBondStrength(kJmol-1)
Study:somehighlyfluorinatedchemicalsarehardertofilterfromwater,http://michiganradio.org/post/study-some-highly-fluorinated-chemicals-are-harder-filter-water
Chirality
Organic Chemistry Concepts:• Chirality
• Identify chiral center• How many stereoisomers?
Toxicology Concepts:• Structure and function
Toxicity: adashorawedge?Readsection4.2.1.1,page5851aboutthetoxicokinetics andtoxicodynamics ofThalidomideRandSenantiomers.Listthedifferencesbetweenthetwoenantiomersintheirtoxicityandefficacy.
N
O
ONH
O
O
thalidomide
HO
HO
HN
OH
albuterol
O
HOH
H
N CH3
HO
morphine
Voutchkova,AdelinaM.;Osimitz,ThomasG.;Anastas,PaulT.“TowardaComprehensiveMolecularDesignFrameworkforReducedHazard” Chem.Rev. 2010,110,5845-5882.
Chirality
Questions:1)Otheropiatederivativesthatareclosestructuralrelativestomorphinearelistedbelow.Useyourfavoritesearchenginetofindthestructuresofeachofthesecompoundsanddrawtheminthecorrespondingboxes.Labeleachstereocenter withthecorrectR orS designation.
2)Interestingly,diamorphinecanbeprescribedintheUKtoalleviatepain.Wheninjectedintoavein,diamorphineis2-3timesaspotentasmorphine,meaningsmalleramountsarerequiredtogeneratethedesiredeffectinpatients.Basedontheirstructures,whichcompoundismorewatersoluble?
diamorphine (a.k.a. heroin) etorphine pethidine (a.k.a. demerol)
Electrophilic-NucleophilicReactions
Organic Chemistry Concepts:• Electrophiles and Nucleophiles• Reactions (SN1, SN2, Acylation, Michael
Addition, Schiff Base Formation, SNAr)
Toxicology Concepts:• DNA and protein binding• Toxicological reaction mechanisms
MeasurementandEstimationofElectrophilicReactivityforPredictiveToxicity,Cronin,M.T.D.,et.al.,Chem.Reviews,2011, 111,2562-2596.
Electrophilic-NucleophilicReactionsMechanism ProteinBindingReactionSN2
SN1
Acylation
SchiffBaseFormation
MichaelAddition
SNAr
Electrophilic-NucleophilicReactionsHardness(1-4leasttomost)
Aminoacidsites Structure
1 Thiol-groupofcysteine
2 S-atomsofmethionine
3 Primaryamino-groups(e.g.,lysine,arginine)
4 Secondaryamino-groupofhistidine
Electrophilic-NucleophilicReactionsHardness(1-4leasttomost)
Nucleic acidsites Structure
1 Primaryaminegroupsofpurinebases(e.g.,arginine,guanine)
2 In-ringN-atomsofpurineandpyrimidinebases(e.g.,N7ofguanine)
3 O-atomsofpurineandpyrimidinebases(e.g.,O6ofguanine)
4 PhosphateO-atom(P=O)
Electrophilic-NucleophilicReactions
Discussion Questions:• Giventhefollowingxenobioticmolecules,proposewhichofthe6reactionmechanismseachelectrophilewillundergowithacorrespondingbiologicalnucleophile
• Proposeamechanismwithabiologicalnucleophile
Acrolein
Benzoylchloride
Methyliodide
4-nitrochlorobenzene
Electrophilic-NucleophilicReactionsToxicity Reactionsite Mainreactionmechanism
Skinsensitization Chemicallymodifiedskinproteins(e.g., Cys,Lys,orSer residues)leadingtoT-cellmediatedallergicresponse
Proteinhaptenation viaSN2,SNAr,MA,SB,Ac
Respiratorysensitization Chemicallymodifiedproteinsinthelung(e.g., Lysresidues) SB,proteincross-linking,SN1,SN2,Ac
Skinirritation Skinproteinsandlipids inthestratumcorneum SB,SN2,MA,Ac,AN
Elevatedacutetoxicityandcytotoxicity(aquaticorterrestrial)
CellularGSH;interactionwithnucleophiles(-OH,-NH2,-SHgroups)inbiologicalmacromolecules(e.g., inhibitionofacetylcholineesterase)
ElectrophilicreactivityviaSN1,SN2,acylation,MA,SB(incontrasttopolarandunpolar narcosis)
Mutagenicityandcarcinogenicity
DNAorRNAgenemutationviaadductformation,basepairsubstitutions,andframeshifts; interactionwithregulatorymolecules
SN1,SN2,acylation, MA,SB
Chromosomalaberration Alteration ofDNAandsequenceofgeneticmaterial(numberofstructureofchromosomes),whichoftenaltersembryonicdevelopment;inhibitionoftopoisomerasesandinteractionwithnuclearproteinsassociatedwithDNA(e.g.,histoneproteins)
DNAand proteinbindingmechanisms
Hepatotoxicity Attackofhepatocytes,thebileduct,orsinusoidal endothelium,Kupffer,orItocellsby:1)directcellstress,directmitochondrialimpairment,andspecificimmunereactions;2)directanddeathreceptor-mediatedpathwaysleadingtomitochondrialpermeabilitytransition;3)apoptosisandnecrosis
Proteinbinding andreceptor-mediatedmechanisms(e.g.,interactionwithP-450enzymefamily,leadingtodamagedmitochondrialfunctionsandpossibleidiosyncraticeffects)
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