Chem 1140; Bioinorganic Chemistry• Introduction• HSAB• Porphyrins• Zn-EnzymesIntroduction! >30% of proteins in PDB contain a metal! Metals are essential enzymatic cofactors and structuralelements in" Hydrolyses, redox chemistry, signaling" Photosynthesis, aerobic respiration, N-fixation, global chemical turnover! Evolution of life is governed by interactions between organiclife forms and essential inorganic resourcesP. Wipf 1 Chem 1140Hard & soft acids and bases• Use: Define which biological ligands readily interactwith metals• Metals are Lewis acids; ligands are basic• Definitions:– “soft”: large (atomic radius) and electronicallypolarizable– “hard”: small and non-polarizable• Rule of thumb: hard acid/base binds hard base/acid,and vice-versaP. Wipf 2 Chem 1140Hard & soft acids and basesHard-soft acid/base classification of metal ions and ligands importantto bioinorganic chemistry:Metals: LigandsHard: H+, Na+, K+, Mg+, Mn2+, H2O, OH-, MeCO2-, PO43-,Al3+, Ga3+, Ca2+, Cr3+, Co3+, CO32-, NO3-, ROH, R2O, NH3,Fe3+, Tl3+RNH2, N2H4, RO-,, Cl-Borderline: Fe2+, Co2+, Ni2+, NO2-, N2, SO32-, Br-, N3, aniline,Cu2+, Zn2+imidazoleSoft: Cu+, Au+, Cd2+, Pt2+, Tl+, R2S, RS-, RSH, SCH-, H-, R3P,Pb2+, Pt4+, Hg2+CN-, RNC, CO, R-General Trends for Transition Metals• Early Transition Metals Late Transition Metals– Low electronegativities – Higher electronegativities– Higher oxidation states – Lower oxidation states– “Harder” metal center – “Softer” metal centersd3d4d5d6d7d8d9d10d10s121ScScandium22TiTitanium23VVanadium24CrChromium25MnManganese26FeIron27CoCobalt28NiNickel29CuCopper39YYttrium40ZrZirconium41NbNiobium42MoMolybdenum43TcTechnetium44RuRuthenum45RhRhodium46PdPalladium47AgSilver57LaLanthanum72HfHafnium73TaTantalum74WTungsten75ReRhenium76OsOsmium77IrIridium78PtPlatinum79AuGoldGroup 8 MetalsP. Wipf 3 Chem 1140Expected ligand-metal pairsLigandsHard: H2O, OH-, MeCO2-, PO43-,CO32-, NO3-, ROH, R2O, NH3,RNH2, N2H4, RO-,, Cl-Borderline: NO2-, N2, SO32-, Br-, N3, aniline, imidazoleSoft: R2S, RS-, RSH, SCH-, H-, R3P, CN-, RNC, CO, R-N MaminoNHNMimidazoylO Mcarbonyl140-170°OOMOO MOOMcarboxylateantisynO M110-140°phenolateO M110-140°S M110-140°S Malkoxidethiolatethioetherhard hard hardhard soft softhardSulfur Donors• Thiolates: powerful bridging ligands, specially for low oxid. state metal center. • Lower electroneg. relative to “O” means they are better donors • Sulfides: also powerful bridging ligands• Bridging plays crucial role in Bioinorganic Chemistry!!! • Neutral donor dialkylsulfides: “Softer” ligands, more polarizable SRThiolatesMercaptides2e- or 4e- Terminal4e- Bridging6e- Triply bridgingEasily oxidizedto R-S-S-RS2Sulfide4e- Terminal4e- Bridging6e- Triply bridging8e- Quad bridgingM SM SRelativelyrareFeSSSFeFeFeSSRRSSR2-FeSFeSRRRRSSSSSRRS SSSSRRRR2-SFeSFeSFe3-Ferredoxins2Fe(+2)2Fe(+3)Fe/S CubanesP. Wipf 4 Chem 1140In general, alkylated amines are notparticularly good ligands. Mainly owing torelatively short N-C bond and thestereoelectronic problems generated from it.Chelating amines have less steric problemsand are better ligands for transition metalcenters. Primary and secondary amines,however, are susceptible to oxidations:Tertiary amines, on the other hand, are quitestable and not easily oxidized. Chelate effecthelps coordinate metals more stronglyPerhaps most famous neutral “N” donor ligandis bipyridine or bipyridyl, abbreviated bipy.Phenanthroline is a more rigid version thatforms even stronger metal chelates.NH2MH2N2+- 4e-M=RuNHMHN2++ 4H+Di-imine ComplexNRRRN NMeMeMeMeTMEDA = tetramethylethylenediaminechelate effect helpscoordinate metals more stronglyN N N NBipy = Bipyridine Phen = phenanthrolineNeutral Nitrogen Donors• Common metal geometries-VSEPR: maximizespace between ligands-ligand field theory:maximize ligand fieldstabilization energy(i.e., maintain lowestenergy d-orbitalconfiguration)P. Wipf 5 Chem 1140Nucleic acid basessofthardhardIrving-Williams series- Ca2+ < Mg2+ < Mn2+ < Fe2+ < Co2+ < Ni2+ < Cu2+ > Zn2+• Use: Define which bio-ligands will be found bound to which metals• Definition: Binding preference, for a given ligand, of divalent first rowtransition metals• Related to decrease in ionic radii across the series, leading to stronger metal-ligand bonds• Rule of thumb: smaller ionic radius, more focused + charge, stronger bonds• Second, third row TMs:Which metal is best for polarizing the carbonyl? P. Wipf 6 Chem 1140Lewis acidity follows series- Ca2+ < Mg2+ < Mn2+ < Fe2+ < Co2+ < Ni2+ < Cu2+ > Zn2+How strong is the effect? Chelate effect- definition of chelation: coordination of two or more donor atoms from asingle ligand to a central metal ion- chelation lowers binding energy and increases binding affinity of ML- reason for: favorable entropic factor accompanying release of nonchelatingligands, e.g. water- examples: EDTA, corrin, porphyrin- catechol + Fe3+, versus hexadentate siderophore KD = 10-35!What’s thecharge on the complex?P. Wipf 7 Chem 1140Proteins as ligands- enhanced chelate effect- exquisite redox tuning from second sphere ligands-!channels, pockets, binding pockets to bind or exclude ligands, waterPorphyrins• Fe– Oxygen Transport• Hemoglobin– 4 Fe containing globin units (2-alpha and 2-beta)– K increases with each O2 added– Fe(II) does not oxidize to Fe(III)» Non-aqueous or simultaneous oxygen binding to twohemes.– Oxygen Storage• Myoglobin– 1 heme groupP. Wipf 8 Chem 1140NNNHNN NN Nimidazolatepyrimidine purineNHN HNN12345678Porphine(metalloporphyrin when bound to a metal)NN NNNN NNFeSProteinSProteinCOOHHOOCCytochrome-CSProteinHOOCHOOCFeFe-protoporphyrin IXBiologically ImportantN-LigandsP. Wipf 9 Chem 1140Oxygen Carrier in Sea WormsOxygen hemocyaninmollusks and arthropodsP. Wipf 10 Chem 1140Iron Environment inMyoglobinCytochromes, Peroxidases, andCatalases• Cytochrome P-450– Oxidation catalyst• Peroxidases/Catalases– Decomposition of organic peroxides.P. Wipf 11 Chem 1140Cytochrome P-450CYP3A is responsible for metabolism of >60% of all drugsWillson, T. M.; Kliewer, S. A. Nat. Rev. Drug Disc. 2002, 1, 259-266.Drug ACYP3ALiver, intestinePXR RXRCYP3AenzymeDrug B HOEthinylestradiol Efavirenz WarfarinErythromycin Cyclosporin TamoxifenAtorvastatin Carbamazepine DoxorubicinIndinavir Drug BP. Wipf 12 Chem 1140Zinc and Copper• Zinc is found in more than 80 different