Lecture 26, December 3, 2009 Nature of the

Lecture 26, December 3, 2009 Nature of the

Lecture 26, December 3, 2009 Nature of the Chemical Bond with applications to catalysis, materials science, nanotechnology, surface science, bioinorganic chemistry, and energy Course number: KAIST EEWS 80.502 Room E11-101 Hours: 0900-1030 Tuesday and Thursday William A. Goddard, III, [email protected] WCU Professor at EEWS-KAIST and Charles and Mary Ferkel Professor of Chemistry, Materials Science, and Applied Physics, California Institute of Technology Senior Assistant: Dr. Hyungjun Kim: [email protected] Manager of Center for Materials Simulation and Design (CMSD) Teaching Assistant: Ms. Ga In Lee: [email protected] Special assistant: copyright Tod Pascal:[email protected] EEWS-90.502-Goddard-L15 2009 William A. Goddard III, all rights reserved 1 Schedule changes Dec. 3, Thursday, 9am, L26, as scheduled Dec. 7-10 wag in Pasadena; no lectures, Dec. 14, Monday, 2pm, L27, additional lecture, room 101

Dec. 15, Final exam 9am-noon, room 101 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 2 Last time EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 3 Bonding in metallic solids Mosty of the systems discussed so far in this course have been covalent, with the number of bonds related to the number of valence electrons. Thus we have discussed the bonding of molecules such as CH4, benzene, O2, and Ozone.. The solids such as diamond, silicon, GaAs, are generally insulators or semiconductors We have also considered covalent bonds to metals such as FeH+, (PH3)2Pt(CH3)2, (bpym)Pt(Cl)(CH3), The Grubbs Ru catalysts We have also discussed the bonding in ionic materials such as

(NaCl)n, NaCl crystal, and BaTiO3, where the atoms are best modeled as ions with the bonding dominated by electrostatics Next we consider the bonding in bulk metals, such as iron, Pt, Li, etc. where there is little connection between the number of bonds and the number of valence electrons. 4 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved Bringing atoms together to form the solid As we bring atoms together to form the solid, the levels broaden into energy bands, which may overlap . Thus for Cu we obtain Energy Fermi energy (HOMO and LUMO Thus we can obtain systems with no band gap. EEWS-90.502-Goddard-L15

Density states copyright 2009 William A. Goddard III, all rights reserved 5 Metals vs inulators EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 6 conductivity EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 7 The elements leading to metallic binding There is not yet a conceptual description for metals of a quality comparable to that for non-metals. However there are some trends, as will be described

EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 8 Body centered cubic (bcc), A2 A2 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 9 Face-centered cubic (fcc), A1 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 10 Alternative view of fcc

EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 11 Closest packing layer EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 12 Stacking of 2 closest packed layers EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 13 Hexagaonal closest packed (hcp) structure, A3

EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 14 Cubic closest packing EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 15 Double hcp The hexagonal lanthanides mostly exhibit a packing of closest packed layers in the sequence ABAC ABAC ABAC This is called the double hcp structure EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved

16 mis fcc hcp bcc Structures of elemental metals some correlation of structure with number of valence electrons EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 17 Binding in metals Li has the bcc structure with 8 nearest neighbor atoms, but there is only one valence electron per atom. Similarly fcc and hcp have 12 nearest neighbor atoms, but Al has

only three valence electrons per atom. Clearly the bonding is very different than covalent One model (Pauling) resonating valence bonds Problem is energetics: Li2 bond energy = 24 kcal/mol 12 kcal/mol per valence electron Cohesive energy of Li (energy to atomize the crystal is 37.7 kcal/mol per valence electron. Too much to explain with resonance New paradigm: Interstitial electron model (IEM). Each valence electron localizes in a tetrahedron between four Li nuclei. + Bonding like in Li , which is 33.7 kcal/mol per valence electron EEWS-90.502-Goddard-L15 2 copyright 2009 William A. Goddard III, all rights reserved 18 GVB orbitals of ring M10 molecules Get 10 valence electrons each localized in a bond midpoint

R=2 a0 EEWS-90.502-Goddard-L15 Calculations treated all 11 valence electrons of Cu, Ag, Au using effective core potential. All electrons for H and Li copyright 2009 William A. Goddard III, all rights reserved 19 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 20 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 21

EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 22 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 23 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 24 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 25 EEWS-90.502-Goddard-L15

copyright 2009 William A. Goddard III, all rights reserved 26 New EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 27 Hypervalent compounds It was quite a surprize to most chemists in 1962 when Neil bartlett reported the formation of a compound involving XeF bonds. But this was quickly folllowed by the synthesis of XeF4 (from Xe and F2 at high temperature and XeF2 in 1962 and later XeF6. Indeed Pauling had predicted in 1933 that XeF6 would be stable, but noone tried to make it. Later compounds such as ClF3 and ClF5 were synthesized These compounds violate simple octet rules and are call hypervalent EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved

28 Noble gas dimers Recall from L17 that there is no chemical bonding in He2, Ne2 etc This is explained in VB theory as due to repulsive Pauli repulsion from the overlap of doubly occupied orbitals It is explained in MO theory as due to filled bonding and antibonding orbitals EEWS-90.502-Goddard-L15 (g)2(u)2 copyright 2009 William A. Goddard III, all rights reserved 29 Noble gas dimer positive ions On the other hand the positive ions are strongly bound (L17) This is explained in MO theory as due to one less antibonding

electron than bonding, leading to a three electron bond for He2+ of 2.5 eV, the same strength as the (g)2(u)1 one electron bond of H2+ The VB explanation is a little Using (g) = L+R and (u)=L-R less straightforward. Here we consider that there are Leads to (with negative sign two equivalent VB structures neither of which leads to much bonding, but superimposing them leads EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved to resonance stabilization 30 Re-examine the bonding of HeH Why not describe HeH as (g)2(u)1 where (g) = L+R and (u)=L-R Would this lead to bonding? The answer is no, as easily seen with the VB form where the

right structure is 23.9 eV above the left. Thus the energy for the (g)2(u)1 state would be +12.0 2.5 = 9.5 eV unbound at R= Adding in ionic stabilization lowers the energy by 14.4/2.0 = 7.2 eV (too big because of shielding) , still unbound by 2.3 eV He EEWS-90.502-Goddard-L15 H He+ IP=+24.6 eV HEA = 0.7 eV 31 copyright 2009 William A. Goddard III, all rights reserved Examine the bonding of XeF Consider the energy to form the charge transfer complex Xe Xe+ The energy to form Xe+ F- can be estimated from Using IP(Xe)=12.13eV, EA(F)=3.40eV, and R(IF)=1.98 A, we get

E(Xe+ F-)=1.45eV Thus there is no covalent bond for XeF, which has a weak bond of ~ 0.1 eV and a long bond EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 32 Examine the bonding in XeF2 We saw that the energy to form Xe+F-, now consider, the impact of putting a 2nd F on the back side of the Xe+ Xe+ Since Xe+ has a singly occupied pz orbital pointing directly at this 2nd F, we can now form a bond to it? How strong would the bond be? Probably the same as for IF, which is 2.88 eV. Thus we expect F--Xe+F- to have a bond strength of ~2.88 1.45 = 1.43 eV! Of course for FXeF we can also form an equivalent bond for F-Xe+--F. Thus we get a resonance We will denote this 3 center 4 electron charge transfer bond as FXeF EEWS-90.502-Goddard-L15

copyright 2009 William A. Goddard III, all rights reserved 33 Stability of XeF2 Ignoring resonance we predict that XeF2 is stable by 1.43 eV. In fact the experimental bond energy is 2.69 eV suggesting that the resonance energy is ~ 1.3 eV. The XeF2 molecule is stable by 2.7 eV with respect to Xe + F 2 But to assess where someone could make and store XeF2, say in a bottle, we have to consider other modes of decomposition. The most likely might be that light or surfaces might generate F atoms, which could then decompose XeF2 by the chain reaction XeF2 + F {XeF + FXeF + F2} Xe + F2 + F Since the bond energy of F2 is 1.6 eV, this reaction is endothermic by 2.7-1.6 = 1.1 eV, suggesting the XeF2 is relatively stable. Indeed it is used with F2 to synthesize XeF4 and 34 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved XeF . XeF4 Putting 2 additional F to overlap the Xe py pair leads to the

square planar structure, which allows 3 center 4 electron charge transfer bonds in both the x and y directions, leading to a square planar structure The VB analysis would indicate that the stability for XeF4 relative to XeF2 should be ~ 2.7 eV, but maybe a bit weaker due to the increased IP of the Xe due to the first hypervalent bond and because of some possible F---F steric interactions. There is a report that the bond energy is 6 eV, which seems too high, compared to our estimate of 5.4 eV. EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 35 XeF6 Since XeF4 still has a pz pair, we can form a third hypervalent bond in this direction to obtain an octahedral XeF6 molecule. Here we expect a stability a little less than 8.1 eV. Pauling in 1933 suggested that XeF6 would be stabile, 30 years in advance of the experiments. He also suggested that XeF8 is stable. However this prediction is wrong

EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 36 Estimated stability of other Nobel gas fluorides (eV) Using the same method as for XeF2, we can estimate the binding energies for the other Noble metals. Here we see that KrF2 is predicted to be stable by 0.7 eV, which makes it susceptible to decomposition by F radicals EEWS-90.502-Goddard-L15 1.3

-2.9 1.3 -5.3 1.3 -0.1 1.3 1.0 1.3 2.7 1.3 3.9 RnF2 is quite stable, by 3.6 eV, but I do not know if it 37 copyright 2009 William A. Goddard III, all rights reserved has been observed

XeCl2 Since EA(Cl)=3.615 eV and R(XeCl+)=2.32A and De(XeCl+)=2.15eV, can estimate that XeCl2 is stable by 1.14 eV with respect to Xe + Cl2. However since the bond energy of Cl2 is 2.48 eV, the energetics of the chain dempostion process are exothermic by 1.34 eV, suggesting at most a small barrier Thus XeCl2 would be difficult to observe EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 38 Halogen Fluorides, ClFn The IP of ClF is 12.66 eV which compares well to the IP of 12.13 for Xe. This suggests that the px and py pairs of Cl could be used to form hypervalent bonds leading to ClF3 and ClF5. Indeed these estimates suggest that ClF3 and ClF5 are stable.

Indeed the experiment energy for ClF3 ClF +F2 is 2.6 eV, quite similar to XeF2. EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 39 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 40 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 41 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 42

EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 43 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 44 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 45 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 46 EEWS-90.502-Goddard-L15

copyright 2009 William A. Goddard III, all rights reserved 47 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 48 Origin of reactivity in the hypervalent reagent o-iodoxybenzoic acid (IBX) Julius Su and William A. Goddard III Materials and Process Simulation Center, California Institute of Technology EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 49 Hypervalent iodine assumes many metallic personalities Oxidations

Radical cyclizations Electrophilic alkene activation CC bond formation O O O OH I CrO3/H2SO4 OAc SnBu3Cl I OAc

OH I HgCl2 OTs O I Pd(OAc)2 Can we understand iodine as we understand metals? Martin, J. C. organo-nonmetallic chemistry Science 1983 221(4610):509-514 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 50 Practical benefits of hypervalent iodine reagents $/mol I 2 Pd 1,300 Os 2,300 Ir

2,700 Pt 2,400 Rh 19,500 oral rat LD50 (mg/kg) I2 14,000 OsO4 162 SeO2 68 Variants possible: water soluble polymer supported non-explosive mixture Cheap, non-toxic, and environmentally friendly. EEWS-90.502-Goddard-L15

copyright 2009 William A. Goddard III, all rights reserved 51 IBX, a single reagent with many roles S OH S OH O O O I OH S 1.1 eq IBX

O 25oC S 78% O 1 eq IBX O 23oC t-Bu t-Bu O 99% conv O

2 eq IBX CHXH oxidations phenols to quinones unsaturation allylic oxidation radical cyclization What is the origin of its diverse reactivity? EEWS-90.502-Goddard-L15 75oC 3 eq IBX 85% CHO 85% 85oC NH 2 eq IBX 90oC

O N O Solvents are DMSO mixtures or CHCl3. Taken from Palmisano, Nicolaou, McFadden. copyright 2009 William A. Goddard III, all rights reserved 86% 52 Theoretical methods Density functional theory Harmonic frequencies Single point continuum solvent Added d and f functions on I Needed for correct bond length and energy, even for covalent iodine bonds b mpw

pw EEWS-90.502-Goddard-L15 Alternative functional MPW1PW91 for better description of long range binding copyright 2009 William A. Goddard III, all rights reserved 53 Validation against experiment and more accurate theory 70 Energy per bond (kcal/mol) Includes atom spin-orbit effects, zero point energy, and BSSE reference 60 50 40 30

our method 20 10 0 IF ICl IBr I2 IOH ICH3 XeF+ XeF2 XeF4 XeF6 XeO XeO3 XeO4 -10 -20 Systematic underestimation of bond energies, but relative energies are accurate. EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved

54 Nature of the hypervalent bond EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 55 Multicenter bonds go beyond the covalent bond H H H H H Strength depends on length only H H

H H H H energy Covalent 2c-2e H 60o bend, 114 kcal/mol Depends on out-of-plane bend too Bond angles and torsions change multicenter bonds. bend (degrees) EEWS-90.502-Goddard-L15 Multicenter 6c-6e

Dijkstra, F. et al. bent benzene Int J. Quan. Chem 1999 74:213221 copyright 2009 William A. Goddard III, all rights reserved 56 Electron rich or poor multicenter bonds: allyl variations MO stabilizations are similar but twisting localizes charge antibonding H H H nonbonding H H

H H H H Etwist H H H H 38 (kcal/mol) EEWS-90.502-Goddard-L15 H H H

H 13 H H H H H localized charge, less stable bonding H H H 33 Electrostatics makes charged

bonds especially stiff. Gobbi et al. allyl resonance J. Am. Chem. Soc. 1994 116:92759286 copyright 2009 William A. Goddard III, all rights reserved 57 Hypervalent bonds as 3c-4e bonds F + F2 h F Xe F F Xe F F

F Xe Xe F F F F F Each lone pair can bond two fluorines (3c-4e bond) valence bond picture molecular orbital picture Resonance stabilized 180o pairs EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved

58 Valence bond explanation of hypervalent bond strengths E = 2 ( covalent + ionic) + resonance covalent = D(XeF+) = 38 kcal/mol ionic = IP(Xe) EA(F) 1/R = +35 kcal/mol resonance = E(180o) E(90o) 71 kcal/mol total

= 74 kcal/mol vs. 62 kcal/mol (expt) = Majority of energy comes from resonance stabilization EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 59 Combining different ligand types I crystal structures covalent EEWS-90.502-Goddard-L15 dative O

F Xe Xe F hypervalent Occupy octahedral positions copyright 2009 William A. Goddard III, all rights reserved 60 Higher order multicenter bonds as transition states F I F F

I F F 3c4e 4c6e F E = 15.5 kcal/mol High symmetry structure has 2nd order Jahn-Teller distortion e* a LUMO e Lower symmetry structure becomes more stable.

EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 61 Valence bond comparison of IF3 geometries In both cases, E = 2 covalent + ionic + resonance To a first approximation, both geometries have the same energy. EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 62 VB explanation of C2v vs. D3h energy difference 90o angle bending 120 o

electrostatic repulsion between ligands E(bend ) E(elec) energies in kcal/mol sum DFT Accounts for all observed energy difference ClF3 4.0 12.3 16.3 16.7

BrF3 5.0 12.0 17.0 17.2 IF 6.4 11.4 17.7William15.4 copyright 2009 A. Goddard III, all rights reserved 3 EEWS-90.502-Goddard-L15 63 Rules of hypervalent reactivity

EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 64 Folk notion of hypervalent bonds as weak and reactive F breaking in oxidation Xe F Eatom = 62 kcal/mol, or 31 kcal/mol per bond creating an ionic fragment single electron

acceptor Proposed mechanisms focus on reactivity of hypervalent bonds EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 65 Rule 1. Individual hypervalent bonds are strong F Xe F F +51 kcal/mol 3e- 2 center bond, resonance lost. EEWS-90.502-Goddard-L15

Xe + F F + Xe + F +8 kcal/mol The first bond is strong, since breaking it creates unstable fragments. copyright 2009 William A. Goddard III, all rights reserved 66 Rule 2: Bonds next to hypervalent bonds are weakened 3e-, 2 center bond is particularly stable 44 kcal/mol 41

Adjacent bond weakened by hypervalent hyperconjugation 13 Hypervalent oxo bond is particularly effective at weakening neighboring bond EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 67 Rule 3. Twist switches hypervalent and covalent ligands hypervalent bonds circled 3c-4e 4c-6e: promotion to higher order hypervalent bond.

3c-4e Twist proceeds via D3h transition state, E = 15.5 kcal/mol EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 68 IBX oxidation of alcohols EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 69 NMR kinetics study of alcohol oxidation O OH O O

I fast O O H HO O R R' H O I R R'

slow OH O I O H2 O R O R' axial geometry Fast ligand exchange followed by slow oxidation Large alcohols oxidize faster than small alcohols De Munari et al, kinetics study J. Org. Chem. 1996 61(26):9272-9276 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved

70 DFT supports ligand exchange preequilibrium O O O O OH2 I O O HOCH3 protonated IBX I

O OH2 + HOCH3 internal ligand rotation E = 7.2 kcal/mol O O I H OCH3 OH2 swapped ligand Calculated dG (kcal/mol) 5.00 Low barrier pathway found,

and good correlation between G (theory) and Keq (expt) 4.00 3.00 2.00 1.00 0.00 0 0.02 0.04 0.06 methanol, isopropanol, t-BuOH benzyl alcohol, etc. Experimental K eq EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 71

Theoretical prediction of alcohol NMR shifts 1 axial geometry equatorial geometry 1 0.8 calc. NMR shielding 0.8 0.6 0.6 0.4 0.4 0.2 0.2

0 0 -0.2 0 0.5 1 0 -0.4 -0.6 -0.6 -0.8 -0.8 measured chemical shift (ppm)

0.4 0.6 0.8 1 -0.2 -0.4 -1 0.2 -1 Confirms that axial species predominates in solution EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 72 An oxidation mechanism with a

twist H H O +CH3OH OH O O I -H2O H O O O O axial

I hypervalent twist OH O O O I O O H H O I H O H

H equatorial Complex must twist for oxidation to happen EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 73 Twisting switches strong and weak bonds We find activating reactivity by twisting to be a common theme EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 74 Twisting 9.9 kcal/mol

Oxidation Ligand exchange 2.6 kcal/mol 7.2 kcal/mol (with H+) O O H O OH O O I -H2O H O O

O H O H H O +CH3OH O I H I OH Hypervalent twisting is ratelimiting

EEWS-90.502-Goddard-L15 O O copyright 2009 William A. Goddard III, all rights reserved I O H H 75 Size selectivity explained, and an improved reagent? repulsion relieved Large alcohols oxidize faster because they twist more easily. OR' O

EEWS-90.502-Goddard-L15 O I OR An ortho group should accelerate twisting further. copyright 2009 William A. Goddard III, all rights reserved 76 Screening for an optimal ortho substituent 4.5 better twisting R' 4.0 B(OH)2

Ph better alcohol/water exchange O HO I 3.5 O 3.0 2.5 O 2.0 tBu best 1.5

B(Ome)2 1.0 Me Et 0.5 Cl 0.0 H -7.0 -6.0 F -5.0 -4.0 -3.0 iPA

-2.0 -1.0 0.0 Large enough to favor twisted structure But not so large it hinders alcohol/water exchange -0.5 Medium-sized aliphatics (Me, Et, i-Pr) best EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 77 Predicted rate acceleration for orthomethyl IBX 6 H3C HO

predicted log(kalc /kMeOH ) rate-limiting ligand exchange twisting O I 5 O 4 3 100x faster rate! 2 1 ipa 0

-1 iso 0 et neo O ph 2,4 1 -1 measured log(kalc/kMeOH) EEWS-90.502-Goddard-L15 HO O O I O 2 Up to 100x faster, then limited by

ligand exchange rate copyright 2009 William A. Goddard III, all rights reserved 78 Other predictions n Etwist Eelim O 2 - 21.9 I 3

- 12.8 4 5.9 4.8 5 5.5 3.8 group Gtwist none 12.1 o-CH3

9.7 o-F 12.1 m-CH3 13.8 m-F 13.9 EEWS-90.502-Goddard-L15 O O n O Minimum chain length needed for oxidation

Meta substituents inhibit twisting, for unknown reasons copyright 2009 William A. Goddard III, all rights reserved 79 Other reactions of IBX EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 80 More complex reactions of IBX OH O O O

IBX NH N O O O HIO3DMSO H Can we explain mechanism and reagent scope? Nicolaou, K. C. et al, allylic oxidation J. Am. Chem. Soc. 2001 123:2183-3185 Nicolaou, K. C. et al, HIO3 reactivity Angew. Chem. Int. Ed. 2002 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 81 Evidence for a single-electron-transfer mechanism Radical clock moiety fragments: Ph

Ph H Ph H Ph O O IBX Ph O Ph H Hammett plot mildly e deficient resonance-stabilized TS: IBX-mediated cyclization,

= 1.4 But EA(IBX-OMe) = 14 kcal/mol, while IP(substrate) = 187 kcal/mol Experiments suggest yes, but theory says no. EEWS-90.502-Goddard-L15 Nicolaou, K. C. et al, SET model J. Am. Chem. Soc. 2002 124(10):22452258 copyright 2009 William A. Goddard III, all rights reserved 82 Proposed mechanism for phenol oxidation O OH MeO O IBX

MeO OMe O O O I O B [2,3] O first oxidation O I

O O O OH I O O second oxidation OMe O I O B H OMe

O HO OMe variant trapped as Diels-Alder adduct breaking both hypervalent bonds at once is okay Diels-Alder adduct strongly suggests [2,3] involved. Magdziak, D. et al, phenol oxidation Org. Lett. 2002 4(2):285-288 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 83 With theory, IBX adducts readily undergo [2,3] Twisting and [2,3]

rearrangement occurs in one step. [2,3] twist Transition states: E = 3.0 kcal/mol EEWS-90.502-Goddard-L15 E = 5.5 kcal/mol copyright 2009 William A. Goddard III, all rights reserved 84 Theoretical Hammett analysis of [2,3]/twist step 2.5 log (k/k0) OMe 2 Et

HO 1.5 R 1 0.5 F -1 p+ 0 -0.5 0 -0.5 0.5 1

Cl NO2 -1 experiment, THF -1.4 theory, gas phase -1.7 theory, THF -2.1 typical SN2 -2.8 typical cation -4.5

-1.5 R [2,3]/twist Small negative mildly electron deficient resonance stabilized SET O O O I R O O O

O I O Small negative equally well supports [2,3]/twist EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 85 Proposed mechanisms for IBX reactions Alcohol oxidation , oxidation Radical cyclization EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 86

Can now explain most known IBX reactions Key step is either twist + elimination or twist/[2,3] EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 87 Reagent scope of IBX versus HIO3DMSO explained no twist possible, only free rotation can twist can perform alcohol oxidation allylic oxidation dehydrogenation radical cyclization needs twist dehydrogenation

radical cyclization (predicted) doesnt need twist HIO3 cannot twist, so is limited to [2,3]/twist reactions EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 88 Allylic oxidation Me CHO 3 eq IBX 85% yield, similar results with 25 substrates. 12 h/85oC DMSO

IBX may generate hydroxy radical in situ: O O I O O OH O I stable, like nitroso O + OH

performs allylic oxidations? Otherwise, we still cannot explain this reaction Nicolaou, K. C. et al, allylic oxidation J. Am. Chem. Soc. 2001 123:2183-3185 EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 89 A new IBX reaction? EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 90 IBX as a generator of alkoxy radicals When no hydrogens or double bonds are available, we predict thermal homolysis can occur to generate radicals. BDE (kcal/mol) IBX-OMe (untwisted)

IBX-OMe (twisted) HO-OH AcO-OAc HO-ONO EEWS-90.502-Goddard-L15 60 33 49 38 22 Homolysis only favored in the twisted form of IBX. copyright 2009 William A. Goddard III, all rights reserved 91 Propose experiments to detect or trap alkoxy radical (most direct) Spin trapping with PhNO, EPR detection Catch radical in fastest manner possible:

O O O I OtBu O O O I O O O Cyclization with substrate free from other side rxns: HO

O Looking for way to exploit or clearly demonstrate this pathway EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 92 Anticancer warheads cause dsDNA damage Bleomycin A2 Dynemicin Propose one based on distortions of hypervalent bonds EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 93 A warhead that releases alkoxy radicals when triggered cleavable tether no hydrogens

or unsaturation imine hydrolysis + Cleaving tether enables twist and homolysis EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 94 Conclusion s Hypervalent bonds are strong, and weaken adjacent bonds Twisting allows the interchange of hypervalent and adjacent bonds, and is the rate-limiting step in many reactions. In IBX reactions, -elimination or [2,3] rearrangement is the key step. EEWS-90.502-Goddard-L15

copyright 2009 William A. Goddard III, all rights reserved 95 Acknowledgements Prof. William A. Goddard III Prof. Brian Stoltz Ryan McFadden EEWS-90.502-Goddard-L15 copyright 2009 William A. Goddard III, all rights reserved 96

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