From Diels-Alder to ozonolysis: An overview of cycloaddition reactions and a brief history of ozonolysis Group Meeting Daniel T. Seidenkranz September 17, 2014 Outline • Cycloaddition reactions What are they and why are they important • Woodward-Hoffman Rules How to construct qualitative MO diagrams Correlation Diagrams Examples • Ozonolysis Brief history Criegee Mechanism Modern Ozonolysis Generation of Ozone Cycloaddition Reactions: What are they?
Cycloaddition Reactions Reaction • Concerted reactions that have a Types cyclic transition states • Sometimes asynchronous • Typically 2 reactants 1 product • Governed by conservation of Polar Pericyclic Redox orbital symmetry • Exchange π bonds for σ bonds • Perpendicular planes
Sn1, Sn2 Electrocyclic
E1, E2 Cycloaddition
Fleming, I. Pericyclic reactions; Oxford University Press, 1998 The Types of Cycloaddition Reactions
[2+2+2] [4+2]
1,3- dipolar cycloaddition
Forbidden [2+2] 1,5-dipolar cycloaddition Soeta, T.; Tamura, K.; Ukaji, Y. Org. Lett. 2012, 14, 1226–1229 Galan, B. R.; Rovis, T. Angew. Chem. Int. Ed. 2009, 48, 2830–2834 The Utility of Cycloaddition Reactions
• Synthesize diverse terpenes • Anit-tumor agents
Gordaliza, M. Mar. Drugs 2012, 10, 358–402 The Utility of Cycloaddition Reactions
Last step in synthesis of Synthesis of spirooxindoles- antimalerial artemisinin antiproliferative drugs
(+)-artemisinin
Van Ornum, S. G.; Champeau, R. M.; Pariza, Narayan, R.; Potowski, M.; Jia, Z.-J.; Antonchick, A. P.; R. Chem. Rev. 2006, 106, 2990–3001 Waldmann, H. Acc. Chem. Res. 2014, 47, 1296–1310 The Utility of Cycloaddition Reactions
• Rhodium catalyzed [2+2+2] cycloadditions to give substituted benzenes
• Good to high yields
• Regioselective
Galan, B. R.; Rovis, T. Angew. Chem. Int. Ed. 2009, 48, 2830–2834 1,3-dipolar Cycloadditions: Types of 1,3-dipoles
Many types, but some more stable than others
Resonance hybrid more accurately depicted as octet structure
Padwa, A. 1,3-dipolar cycloaddition chemistry; Wiley, 1984; Vol. 1 1,3-dipolar Cycloadditions: Nucleophilicity and Electrophilicty
Both ends can be nucleophilic
Both ends can be electrophilic
Ambivalence is not necessarily equivalent Electrophilicity ≠ Nucleophilicity
Padwa, A. 1,3-dipolar cycloaddition chemistry; Wiley, 1984; Vol. 1 Types of 1,3-dipolar cycloaddition orbital interactions
Padwa, A. 1,3-dipolar cycloaddition chemistry; Wiley, 1984; Vol. 1 1,3-dipolar Cycloadditions: More Nucleophilic Dipoles
• Negative slope=positive charge build up in TS
• kEDG> kEWG for substituted dipole • Supports notion of a high energy HOMO • More nucleophilic dipoles
Padwa, A. 1,3-dipolar cycloaddition chemistry; Wiley, 1984; Vol. 1 display type I reactivity Huisgen, R.; Geittner, J. Heterocycles, 1978, 11, 105-108 1,3-dipolar Cycloadditions: More Electrophilic Dipoles
• Negative slope = positive charge in TS
• kEDG > kEWG for dipolarophile • Supports notion of a low energy LUMO • More electrophilic dipoles display type III reactivity Papalambros, L.; Nikokavouras, J. J. Photochem. 1987, 39, 73–84 1,3-dipolar Cycloadditions: Nucleophilic and electrophilic dioples
• Very little slope = no electronic de/stabilization of TS.
kEDG ≈ kEWG
• Supports notion equally spaced HOMO/LUMO gaps • Display type II reactivity
Padwa, A. 1,3-dipolar cycloaddition chemistry; Wiley, 1984; Vol. 1 1,3-dipolar Cycloadditions: Regiochemical control
Proof
If cL > cs then − > 0
Expand + − 2 > 0
Rearrange + > 2
• Determined by MO coefficients on FMO • Orbital coefficients can be calculated or estimated by electronegativity difference
Padwa, A. 1,3-dipolar cycloaddition chemistry; Wiley, 1984; Vol. 2 Outline • Cycloaddition reactions What and why • Woodward-Hoffman Rules How to construct qualitative MO diagrams Correlation Diagrams Examples • Ozonolysis Brief history Criegee Mechanism Modern Ozonlysis Generation of Ozone Important Nomenclature
π4s
Orbital involved Number of electrons in Addition of groups to orbital(s) component (i.e. direction of attack)
π
σ
ω antarafacial suprafacial Woodward-Hoffman Rules Govern All Cycloaddition Reactions
Pericyclic reactions are thermally allowed if (4q+2)s + (4r)a is ODD
Pericyclic reactions are photochemically allowed if (4q+2)s + (4r)a is EVEN
(4q+2)s - number of suprafacial components whose π electrons = (4q+2) (4r)a - number of antarfacial components whose π electrons = 4r
q and r = any integer
Total π Electron Thermal Photochemical Count - 4q+2 Allowed “Forbidden” Diene = suprafacial, π e = 4 = 4(1) - 4r “Forbidden” Allowed Dienophile = suprafacial, π e = 2 = 4(0)+2
Hoffmann, R.; Woodward, R. B. J. Am. Chem. Soc. 1965, 87, 2046–2048 Fleming, I. Pericyclic reactions; Oxford University Press, 1998 A Quick Interjection: How to Build Qualitative MO Diagrams for π Systems
1. Consider Valance Orbitals only 2. Number of AOs= Number of MOs 3. Form completely delocalized MOs as linear combinations of s and p AOs 4. MOs must be symmetric or antisymmetric w.r.t. the symmetry operations of the molecule 5. If the two highest energy MOs of a given symmetry derive primarily from different kinds of AOs, then mix the two MOs to form hybrid orbitals 6. Antibonding interactions raise orbital energies more than bonding interactions stabilize 7. The more electronegative elements have lower energy AOs
Anslyn, E.; Dougherty, D. Modern Organic Physical Chemistry; 1st ed.; University Science Books, 200 Some Helpful Shortcuts
• The number of nodes for linear π systems with an even number of carbons increases from 0 to n-1. • # of bonding MOs = # of antibonding MOs Helpful Shortcuts Continued
• Odd numbered carbon systems are similar but have 1 n.b. energy level • # of bonding MOs = # of antibonding MOs Using Correlation Diagrams σ σ
Correlation diagrams help determine where the electrons of a reaction must go during the course of a reaction
Orbital symmetry must be preserved
Observe a net lowering of energy
Hoffmann, R.; Woodward, R. B. J. Am. Chem. Soc. 1965, 87, 2046–2048 Correlation Diagram of Ethylene Dimerization
Thermal Photochemical Correlation Diagram of Ozonolysis Outline • Cycloaddition reactions What and why • Woodward-Hoffman Rules How to construct qualitative MO diagrams Correlation Diagrams Examples • Ozonolysis Brief history Criegee Mechanism Modern Ozonolysis Generation of Ozone A Brief History of Ozone and Ozonolysis
Harries begins Rudolf Criegee proposes publishing his work on currently accepted ozonolysis mechanism
1903 1953
1840 1925 Schönbein discovers ozone Staudinger proposes important, but later disproven, mechanism
Bailey, P. S. Ozonation in Organic Chemistry; Academic Press Inc., 1978; Vol. 1 The Staudinger Mechanism
• Incorrectly assigned molozonide as cycloaddition product • Focused on the structure of product from ozone addition
Bailey, P. S. Ozonation in Organic Chemistry; Academic Press Inc., 1978; Vol. 1 The Criegee Mechanism
Bailey, P. S. Ozonation in Organic Chemistry; Academic Press Inc., 1978; Vol. 1 Evidence for the Criegee Mechanism: 1) Cross Ozonides
Control shows no rxn with preformed Similar ozonides derived from different alkenes ozonide products
Thus no intermolecular Bailey, P. S. Chem. Rev. 1958, 58, 925–1010 rearrangement of secondary ozonide Evidence for the Criegee Mechanism: 2) Cross ozonoides
Same ozonide from different alkenes
Implies a common intermediate in both reactions
Bailey, P. S. Chem. Rev. 1958, 58, 925–1010 Evidence for the Criegee Mechanism: 3) Constitutional isomers lead to same ozonide
• If intramolecular rearrangement (not carbonyl oxide) then scrambling of both substrates
• If separate intermolecular attack then no secondary ozonide
• If methyl group ends up on carbonyl then likely proceeds through carbonyl oxide
Bailey, P. S. Chem. Rev. 1958, 58, 925–1010 Modern Ozonolysis
• Typical Reductants and Oxidants • Flow adaptations • Eliminating secondary ozonides Typical Oxidants and Reductants
Oxidants Reductants
Reagent Products Reagent Products
PPh3 Aldehyde/Ketone H2O2 Carboxylic Acid SMe2 Aldehyde/Ketone O2 Carboxylic Acid Silver Oxide Carboxylic Acid Zinc/AcOH Aldehyde/Ketone Permanganate Carboxylic Acid Bis(sulfite) ion Aldehyde/Ketone
NaBH4 Alcohol Methyllithium Alcohol
Bailey, P. S. Chem. Rev. 1958, 58, 925–1010 Flow adaptations: Microreactors
Wada, Y.; Schmidt, M. A.; Jensen, K. F. Ind. Eng. Chem. Res. 2006, 45, 8036–8042. Flow adaptations: Microreactors Benefits High Surface Area: Volume Ratio • High mass transfer rates = more ozone delivered • High heat transfer rates = more effective cooling • Small reaction volumes = safer
* With P(OEt2)3 as quenching agent
Wada, Y.; Schmidt, M. A.; Jensen, K. F. Ind. Eng. Chem. Res. 2006, 45, 8036–8042. Flow Adaptations: Permiable Teflon-AF-2400
• Permeable to gases and not liquids • Subsequent quench
with ssPPh3
O’Brien, M.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2010, 12, 1596–1598. Eliminating Secondary Ozonides: Solubilized Water
Hypothesis
Solubilized H2O will form hyrdroperoxide and decompose to carbonyl faster than secondary ozonide formation
Previously Reported Dussalt Approach Eliminating Secondary Ozonides: Solubilized Water
Good results, but batch scale and limited by solubility
Schiaffo, C. E.; Dussault, P. H. J. Org. Chem. 2008, 73, 4688–4690. Generating Ozone Through a Corona Discharge Large potential difference (20,000 V) + + + + + + + + + O2 in ------O3 out Corona Discharge - an electrical + + + + + + + + + discharge caused by a stream of • Arcing does not ionized fluid ( a plasma) around a occur because conductor electric field is not high enough to supercede the breakdown voltage of air 3,000,000 V/M https://www.youtube.com/watch?v=z9PEJZ0HqVQ Questions
Electron Count Thermal Photochemical 4q+2 Allowed “Forbidden” 4r “Forbidden” Allowed
+ + + + + + + + + Large ------potential difference (20,000 V) + + + + + + + + +