Anchoring Concepts workshop - Beyond Benign

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

?

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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Amy_Cannon@beyondbenign.org