Synthesis and Reactivity of Manganese and Iron Complexes with Methylated Derivatives of Bis(2-pyridylmethyl)-1,2- ethanediamine (bispicen) Christian R. Goldsmith Auburn University Department of Chemistry & Biochemistry

Conversion of Alkane C-H to C-X Bonds Chief industrial method for halogenating aliphatic C-H bonds is free radical halogenation Halogen radicals abstract hydrogen atom from alkane Cl 2 or Br 2 serves as halogen source as well as oxidant Lack of regioselectivity problematic 2

3 Bio-Inspiration: SyrB2 Halogenase The halogenase SyrB2 uses a mononuclear non-heme iron active site to halogenate aliphatic C-H bonds using O 2 and Br/Cl - Crystal structure differs from non-heme iron oxygenases in that Br/Cl atom ligates iron Similar mechanism to  - ketoglutarate dependent hydroxylases proposed Active Fe IV (O)(Cl) species proposed to abstract H atom from L-threonine substrate Blasiak, L. C.; Vaillancourt, F. H.; Walsh, C. T.; Drennan, C. L. Nature 2006, 440, Br/Cl Fe

4 Postulated Enzymatic Mechanism

Previous Successes TPA system reported by Que’s group (Leising, R. A. et al. J. Am. Chem. Soc. 1991, 113, 8555) Iron(II) bispidine catalyst reported by Comba’s group (Comba, P. & Wunderlich, S. Chem. Eur. J. 2010, 16, 7293) Common features: relatively rigid ligands, t-butyl hydroperoxide serves as oxidant 5 Comba, P.; Wunderlich, S. Chem. Eur. J. 2010, 16,

6 Parent Ligand- Bispicen N,N-Bis(2-pyridylmethyl)-1,2-ethanediamine Binds metal ions in cis-  conformation Easy to make Easy to modify –Steric bulk (pyridine rings/amines) –Electronic perturbations Bispicen

7 Methylated Bispicen Syntheses (L Me n) R = H: L Me 2 R = Me: L Me 4 R = H: L Me 1 R = Me: L Me 3 Yields from commercial materials: 67% (L Me 4) and 77% (L Me 3) L Me 2, L Me 2’ and L Me 1 previously made Coates, C. M. et al. manuscript submitted

8 Metal Complex Syntheses Mix ligands, MnCl 2 or FeCl 2, and acetonitrile (MeCN) Heat to dissolve everything, then cool Many compounds crystallize, allowing structural characterization Compounds prepared in yields ranging from 41% to 96% Lowest yields with tetramethylated bispicen derivative (L Me 4) [Mn(L Me 4)Cl 2 ][Fe(L Me 4)Cl 2 ]

9 All compounds high-spin as assessed by M-L bond lengths and magnetic susceptibility Unexpectedly, all three conformational possibilities seen! [M(L Me n)Cl 2 ] Structural Analysis [Mn(L Me 1)Cl 2 ]: cis-  [Mn(L Me 3)Cl 2 ]: cis- 

[M(L Me n)Cl 2 ] Structural Analysis 10 trans conformer seen with L Me 2’ ligand, despite steric clash between 6-methyl groups on pyridine rings Pyridine rings tilt in opposite directions to relieve strain Significant distortion from octahedral geometry Overall geometry best described as pentagonal bipyramidal with missing vertex [Mn(L Me 2’)Cl 2 ]: trans

Solution Dynamics Structures not conserved in solution EPR spectra of manganese complexes not consistent with single mononuclear species 1 H NMR spectra of structurally characterized iron compounds also inconsistent with crystal structures At higher temperatures, 1 H NMR resonances broaden and coalesce 11 EPR spectrum of [Mn(L Me 2)Cl 2 ] in DMF at 50 K L Me 2 =

12 [M(L Me n)Cl 2 ] Electrochemistry M(III/II) potentials generally increase with methylation Methylation weakens ability of ligand to act as  -donor Potentials of iron compounds more strongly impacted by ligand perturbations CV of [Mn(L Me 4)Cl 2 ] in MeCN

Mn-N Bond Lengths Average M-N bond distances generally increase with methylation Comparison complicated by different conformers, crystal packing cis-  conformation appears to allow closer approach of one of the methylpyridines and the non-methylated amine N(4) 13 CompoundM-N(1)M-N(2)M-N(3)M-N(4)M-N avg [Mn(L Me 1)Cl 2 ], unit A2.278(3)2.290(3)2.342(3)*2.307(3)2.304 [Mn(L Me 1)Cl 2 ], unit B2.273(4)2.293(3)2.391(4)*2.311(4)2.317 [Mn(L Me 2)Cl 2 ]2.278(2) 2.366(2)* [Mn(L Me 2’)Cl 2 ]2.4222(11)*2.4182(10)*2.2868(10)2.2874(11)2.354 [Mn(L Me 3)Cl 2 ], unit A2.377(4)*2.439(4)*2.344(4)*2.256(4)2.355 [Mn(L Me 3)Cl 2 ], unit B2.307(5)*2.458(5)*2.343(5)*2.263(5)2.343 [Mn(L Me 4)Cl 2 ]2.4757(10)*2.4703(10)*2.3298(10)*2.3386(10)*2.404 [Fe(L Me 2)Cl 2 ]2.195(4) 2.278(4)* [Fe(L Me 4)Cl 2 ]2.4069(18)*2.4236(19)*2.2689(18)*2.2639(19)*2.341

14 Chlorination Activity- [Fe(L Me 2)Cl 2 ] Hydrocarbon chlorination seen when peracid used as terminal oxidant Metal systems cannot chlorinate cyclohexane but can mildly chlorinate allylic and benzylic substrates [Fe IV (L Me 2)(O)Cl 2 ] seen by optical and mass spectroscopies in absence of substrate, vanishes in under 30 s at RT Reactions run for 60 min under N 2 at 22 °C with MCPBA as terminal oxidant; no additional chloride added Organic products identified and quantified by GC and 1 H NMR BDE of weakest C-H bond(s): Goldsmith, C. R.. et al. manuscript in preparation

15 Regioselecivity? With single equivalent of MCPBA, [Fe(L Me 2)Cl 2 ] chlorinates ethylbenzene (15% yield) but not toluene or cumene With 10 equiv MCPBA, yield of above chlorination reaction with ethylbenzene increases to 83% but with oxygenated byproducts (30% of oxidized substrate) –Toluene chlorinated (20%) with excess oxidant –Cumene still untouched Comparable ethylbenzene reaction with [Mn(L Me 2)Cl 2 ] yields 1- chloroethylbenzene in 2% yield {with excess oxidant}

16 Conclusions The bispicen framework is more flexible than previously thought and is able to accommodate metal ions in at least three distinct conformations: cis- , cis- , and trans –EPR and NMR demonstrate that these solid-state structures are not exclusively maintained in solution The M(III/II) potentials generally increase with ligand methylation, consistent with steric effects weakening the  -donation from the N- donors to the metal ion The [Fe(L Me 2)Cl 2 ] reacts with MCPBA to chlorinate benzylic substrates via an [Fe IV (L Me 2)(O)Cl 2 ] species, albeit poorly –Iron outperforms manganese –The oxidant seems to have a preference for activating C-H bonds on secondary carbons (ethylbenzene) –Flexibility of ligand may facilitate its degradation

17 Acknowledgements Personnel Dr. Cristina M. Coates (AU, now at Nicholls State University) Dr. John D. Gorden (AU) Prof. Thomas E. Albrecht-Schmitt (University of Notre Dame) Prof. Evert Duin (AU) Kenton Hagan (Huntington College) Casey A. Mitchell (AU) Funding Auburn University AU Cell and Molecular Biosciences Program (NSF EPS ) American Chemical Society-Petroleum Research Fund

[Fe(L Me 2)(O)Cl 2 ] 0.32 mM [Fe(L Me 2)Cl 2 ] mM MCPBA in MeCN Intermediate observed at 5 s (scan B in UV/vis) Associated with transient feature in MS with m/z ratio of

19 Chlorination of Toluene Derivatives CatalystSubstrateAlcoholCarbonylChloride NoneToluene0 mM0 mM0 mM FeCl 2 Toluene [Fe(L Me 2)Cl 2 ]Toluene [Fe(L Me 4)Cl 2 ]Toluene NoneEthylbenzene7.700 FeCl 2 Ethylbenzene [Fe(L Me 2)Cl 2 ]Ethylbenzene [Fe(L Me 4)Cl 2 ]Ethylbenzene NoneCumene5.0n/a0 FeCl 2 Cumene 42.0n/a8.9 [Fe(L Me 2)Cl 2 ]Cumene0n/a0 [Fe(L Me 4)Cl 2 ]Cumene 0n/a0