Chemistry 125: Lecture 51 February 14, 2011 Cycloaddition Epoxides Ozonolysis & Acetals CH 3 Li + O=CH 2 Analogy OsO 4 This For copyright notice see final page of this file

Other “Simultaneous” Reagents Cl 2 C: (Carbene) R 2 BH (Hydroboration) CH 2 I 2 Zn/Cu (Carbenoid) O 3 (Ozonolysis) H-metal (Catalytic Hydrogenation) R-metal (Metathesis, Polymerization) RC (Epoxidation) OOHOOH O

CH 2 H2CH2C H2CH2C O O O C H H All happen together with minimal atomic displacement (but not strictly in parallel)     Wouldn’t it have been simpler to abbreviate arrows as in textbooks?    (  &  are defined with respect to the plane of the peroxyacid nuclei)

polyethers – 3 to >20,000 units (solvents) or H+H+ H + Catalysis H2CH2CCH 2 O HO - 20,000,000 tons $20 billion per year H2CH2CCH 2 O ethylene glycol (antifreeze, solvents, polymers) e.g. J&F Sec. 10.4c pp H2CH2CCH 2 HO OH H2OH2O of which 2/3 H2CH2CCH 2 O HO - Catalysis H2CH2CCH 2 O H + H2CH2C HO OH H2OH2O - HO - H2OH2O H2CH2CCH 2 HO OH - H + ring strain good leaving group Org Syn Prep (click) OH H2CH2CCH 2 -O-O Cl - K +

Regiospecificity 55 / 45 =  E a = 0.12 kcal/mole

Protonated Isobutylene Oxide 1.47Å1.61Å worst place for H + best place for Nu -

Cuprates (Carbon Nucleophiles) Stereospecificity More Impressive Regiospecificity J&F sec 10.5c 430

Ozonolysis by Cycloadditions e.g. J&F sec 10.5a

Concerted Transition State (calc by quantum mech) H2CH2C CH 2 O O O + _

Motion along Reaction Coordinate through Transition State O3O3 C2H4C2H4 side viewend view

HOMO LUMO HOMO Transition State Orbital Mixing makes two new bonds O3O3 C2H4C2H4 HOMO LUMO HOMO-1

Cycloaddition of Allylic 1,3-Dipoles to Alkenes 7 O O O + O O O + O O O + O O O + open structure of O 3 (Cf. Lecture 3)

Ozone (O 3 ) from the “top” (rotate back at the top to view the 3  MOs made from the 3 “allylic” out-of-plane 2p orbitals of the 3 O atoms)  1 No ABN (anti-bonding node) Middle AO is largest (it overlaps twice)  2 One ABN node. Middle AO is absent. No significant overlap, thus ~ same energy as isolated 2p AO.  3 Two ABNs - highest energy  MO. (I’m not sure why the middle AO looks about the same size as the terminal ones, it must be larger in order for  3 to be orthogonal to  1.)

Another allylic system CH 2 -BH-CH 2 from “top” (rotate back to view 3  MOs)  1 (middle B AO about same size as C AOs; overlaps twice, but has lower nuclear charge)  2 Note how C AOs look larger than O AOs of O 3, because C AO is less dense near the nucleus)  3 Most of the lower-energy C AOs were used up in  1 and  2.

 1 Partly C AO just looks big (but also C=O is short, which makes CO overlap important)  2 node no longer in exact center  3 BIG C AO for this high- energy MO H 2 C=O O + - “carbonyl oxide” pOpO  C=O  * C=O Central O overlaps C better than O, so view as right O interacting weakly with C=O orbitals. 11 22 33 more mixing (better E-match) less mixing pOpO pCpC  * - p O  - p O  + p O  - p O  * - p O

.. Number of  electrons LUMO HOMO LUMO (ends match  * alkene LUMO) (ends match  alkene HOMO) (ends match  alkene HOMO) (No alkene HOMO match) (No alkene LUMO match).. Can’t make two bonds simultaneously for cycloaddition to alkene!.. HOMO LUMO (ends match  * alkene LUMO) * * Don’t worry about apparent bad overlap with the blue lobe of the central oxygen. It is far enough away because of the bend in O 3. O O O 4 C B C H HH H H H O O H C Makes two bonds

CH 2 H2CH2C O O O + Ozonolysis e.g. J&F Section 10.5a, pp

O CH 2 H2CH2C O O : Undergoes a “reverse” of the previous process. “Molozonide” is rather unstable because of HOMO-HOMO mix in -O-O-O- group. Ozonolysis

CH 2 O O H2CH2C O + O Undergoes a “reverse” of the previous process. to give carbonyl oxide and C=O Re-adds after rotation (avoids -O-O-O-) Ozonolysis

CH 2 O-O O H2CH2C Ozonide a Double Acetal Ozonolysis

Process? Mechanism for Acid-Catalyzed Hydrolysis of Acetal RO CH 2 + H HOH : : RO CH 2 + HROH RO-CH 2 + HO RO CH 2 + H First remove RO, and replace it by HO. HO RO CH 2 Now remove second RO, then H (from HO) : HO RO CH 2 + H RO=CH 2 + cation unusually stable, thus easily formed ROH H-O-CH 2 + O=CH 2 ROH : Overall Transformation: H 2 O + Acetal Carbonyl + 2 ROH H+H+ (e.g. J&F pp ) (hemiacetal) Process? SN1SN1 E1 + H O H H CH 2 RO

HOHO O=CH 2 CH 2 HO-O O H H O-O O H2CH2C O H H H H H 2 C=O Ozonide is a Double Acetal So Double Hydrolysis and hydrogen peroxide Gives Two Carbonyl Compounds which oxidizes aldehydes to carboxylic acids! Ozonolysis

e.g. J&F Sec. 10.5b pp Add a reducing agent like (CH 3 ) 2 S (or Zn) to destroy HOOH and save RCH=O. Or go with the flow and add more HOOH to obtain a good yield of RCOOH. Ozonolysis

3-membered ring with O-O bond is even worse. What Happens to HOOH + RCHO? O C H R O OH - O C H R O - O C H R O - HOH - O CR O R B R R O OH - Cf. Problem: Try drawing an analogous acid-catalyzed mechanism in which HOOH attacks the protonated carbonyl, then H + is lost from one O of the HOOH fragment in the product and added to the other before rearrangement. OH OH - is a bad leaving group from C, but O-O bond is very weak. Hydride Shift

“Nucleophilic” Addition to C=O

The nucleophilic addition of methyl lithium to carbonyl groups* is formally quite different from these additions of electrophiles to alkenes, but the following transition state analysis reveals a marked mechanistic similarity. * which will be discussed in more detail later.

Transition State Motion Li-CH 3 O=CH 2 Li CH 3 O CH 2

Transition State Orbital Mixing Li-CH 3 O=CH 2 HOMOLUMO+2  * LUMO  HOMO

Orbital Variety from Metals

overlaps with alkene  *overlaps with alkene  LUMOHOMO Os or Mn - OsO 4 and Permanganate e.g. J&F Sec. 10.5c p. 443

OsO 4 and Permanganate Os analogue of cyclic acetal H-O-H e.g. J&F Sec. 10.5c p. 443 Osmate Ester H H C C H3CH3C CH 3 H H C C H3CH3C OO O O Os O O OO O HH

Abigail Batchelder

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