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Academ Present 022009 001[1]
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2. Horner-Wittig Reagents in Sulfur and Selenium Chemistry Pieter Otten and Arne van der Gen Leiden Institute of Chemistry Leiden University, The Netherlands P S Se
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4. Thioamide Synthesis Aminomethylphosphine oxides, excellent reagents for enamine formation, show a unique reactivity towards chalcogens to form amides R = aryl: reaction at r.t R = alkyl: reaction at 0 o C to quell deprotonation of formed thioalkanamides by the HW reagent
5. Selenoamide Synthesis “ Red selenium”, Se 8 , more reactive than metallic or gray Se; allows isolation of acidic selenoalkanamides at lower temperatures Reaction is sluggish at ambient.
6. Mechanistic Considerations One eq. of S gives < 50% yield, recover phosphine oxide All intermediates isolated and characterized. Mass balance accounted for. Intermediate trapped at low temperatures with MeI Independently confirmed
7. Crystal Structure Selenobenzamides Amino group reduces dihedral angle C=Se: 1.840 Å C-N: 1.331 Å = 53.3º C=Se: 1.824 Å = 81.1º C(5) is sp 2 -hydrid.
9. VT 13 C NMR Study: Rotational Barriers C=S and C=Se strongly e-withdrawing groups, + p fits only More polarizable Se more sensitive to + p than S o = Se * = S Eyring eq.: G* rot = 19.5T c x [9.971 + log(T c / )]
12. Mechanistic Considerations (Curtin-Hammett Principle) Trapped HW-adducts (R3 = Ph -60 o C, H 2 O): R1 = n-Pr: pro(E)/pro(Z) = 1/1, quant. R1 = c-Hex: pro(E)/pro(Z) = 1/1+ 22% (E)-vinyl selenide! Sterics facilitate elimination, k E increases R1 = phenyl, pro(E)/pro(Z) = 3/2. quant, pro-(E) and pro(Z) must rapidly equilibrate via reverse to aldehyde and/or epimerization and (E)-isomer is thermodynamic sink pro-(E) Pro-(Z)
13. Do HW adducts equilibrate? No vinyl selenide derived from propionaldehyde observed: no equilibration via reverse reaction with aliphatic aldehydes. Cannot rule out epimerization. Fast equilibration with aromatic aldehydes to explain discrepancy between pro-(E) and pro-(Z) ratio for isolated HW adduct (3/2) and strong E-selectivity for completed HW reaction.
14. Alternate Intermediate Warren proposes this late-stage intermediate to explain high pro-(Z) selectivity for simple alkyl phosphine oxides (R1 = alkyl) Pro-(E) Six-centered transition state. R1 equatorial to avoid 1,3-interaction with equatorial Ph. Low energy difference between SeR3 equatorial or axial, reflected by observed low stereoselectivity In HW-adducts. Pro-(Z)
17. Crystal Structure Confirms Z-geometry P -1 , a = 13.3146, b = 11.326, c = 9.395 Å; = 125.15 = 97.88, = 96.76; V = 1097.45 Å 3 , Z = 4, = 1.396 kg/dm 3
18. Mechanistic Considerations Phosphine oxide anion and carbonyl are in equilibrium w/ adduct. Fast when R1 = anion stabilizing aryl Rotation sets up for the oxaphosphetane. Sterics favor pro-(Z) intermediate Thermodynamic sink Elimination fast if R2 stabilizes double bond: aryl, vinyl
19. Mechanistic Considerations: Alternate Approach Surprisingly poor stereochemistry with bulky c-hexanecarboxaldehyde Li + ligated between P=O and S=O. R1 equatorial to avoid axial Ph. Aldehyde approaches with R2 pointing away from axial Ph. Must be an intermediate trough on the energy surface
20. Michael Addition P 2 1 , a = 6.371, b = 7.646, c = 12.364 Å; = 90.0 = 98.45, = 90.0; V = 595.7 Å 3 , Z = 2, = 1.50 kg/dm 3
21. Mechanistic Considerations A compact sodium complex is formed, dictating stereochemistry Malonitrile gives 1:1 mixture of diastereoisomers
22. Synthesis of S , N -ketene Acetals and Thioesters R2=aryl: pure ketene acetale after extractive work-up only. R2=alkyl, contaminated w/ condensation products. Carry thru to thioester for good use
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24. Fluorescent Magnesium Indicators Pieter Otten, Louis Levy, and Robert London, National Institute of Environmental Health Sciences, RTP, NC
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27. Why APTRA (Aminophenol Triacetic Acid)? At physiol. Mg 2+ , BAPTA binds two ions. Cut BAPTA in half to get to APTRA.
28. Pd coupling: fast, one step approach to quickly invest structural diversity
29. Suzuki Coupling K D, Mg = 2.3 mM K D, Ca = 70 M K D, Mg = 2.1 mM K D, Ca = 28 M K D, Mg = 1.8 mM K D, Ca = 17 M
31. Synthesis of 4-Oxo-4 H -quinolizine-3-carboxylates Known complexers of Mg 2+ to shut down bacterial DNA-gyrase w/ K D = 1 mM Explore reactivity to diversify quickly
40. NMR-active, Fluorinated Reporter Molecules Pieter Otten and Ralph P. Mason Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX
43. CF 3 -POL Triple the fluorines, triple the signal Does not penetrate rbc membrane
44. Fluorinated Gene Reporter Saline at 30 o C (♦) Plasma at 30 o C (□) Plasma at 37 o C (Δ) Top: pH = 4.5; t = 30 o C; β-gal ( Aspergillus Oryzae ) Bottom: pH = 7.3 -> 6.8; t = 37 o C; β-gal ( E. Coli ) pK a = 6.85