Radical Reactions. Radical Stability!!! bond dissociation energies X Y X + Y. bond BDE (kcal/mol) bond BDE (kcal/mol) CH 3 CH 3 CH 2 95 O H R 2 C H

adical eactions adical Stability!!! bond dissociation energies X Y X Y bond BDE (kcal/mol) bond BDE (kcal/mol) C 3 104 108 C 3 C 2 98 110 95 2 C 102 (-) 93 (C-) 92 C 3 C 3 36 89 85 C 3 C 3 80

adical eactions eaction Types!!! Addition eactions (to C=C, C=, C C, C ) C C C C Abstraction (usually or X) Z Z Bond Cleavage or Electron Transfer e ecombination

adical eactions Carbon adical Addition eactions!!! general features n n - reactions proceed under mild, neutral conditions - radical intermediates well suited to formation of hindered bonds - radical addition to alkene are usually exothermic, irreversible, and have early reactant-like transition states - carbon centered radicals are inert to and 2 - carbon radicals do not undergo β-elimination of or 2 groups - radical centers do not usually retain stereochemistry

adical eactions eneral Principles!!! mechanism driving force: Sn Sn Br BDE = 64 kcal/mol BDE = 60 kcal/mol Br Bu 3 Sn AIB, Δ inititation: C C Δ 2 C 2 azobisisobutyronitrile (AIB) Bn 3 Sn C Bn 3 Sn C Br Bn 3 Sn Bn 3 Sn Br

adical eactions eneral Principles!!! mechanism Br Bu 3 Sn AIB, Δ initiation Br Bu 3 Sn Br propagation Bu 3 Sn Bu 3 Sn termination

adical eactions Intermolecular eactions!!! addition X Bu 3 Sn AIB, Δ rate of addition: C 6 13 to = K rel = 1 84 3,000 8,500 I Bu 3 Sn C AIB, Δ C 95%

adical eactions Intermolecular eactions!!! regioselectivity

adical eactions Intermolecular eactions!!! examples Ac Ac Ac Br Ac C Bu 3 Sn, hν C Ac Ac Ac Ac addition product (55%) Ac Ac Ac Ac reduction product (20%) Bn I (10 equiv) Bu 3 Sn, AIB, Δ 53% Bn 4 steps exo-brevicomin

adical eactions Intermolecular eactions!!! examples Ph * C 9 19 I Et Bu 3 SnCl (0.2 equiv) ab 4 (excess), ab 4 Ph C 9 19 C 2 Et 2 Pd/C 19 C 9 70% malyngolide Et 2 C Et 2 C Cl TMS tbu Bu 3 Sn AIB, Δ Et 2 C Et 2 C TMS tbu 56%

adical eactions X Bu 3 Sn AIB, Δ n Intramolecular eactions!!! n n regiochemistry 100 : 0 3-exo-trig vs 4-endo-trig 100 : 0 4-exo-trig vs 5-endo-trig 98 : 2 5-exo-trig vs 6-endo-trig 85 : 15 6-exo-trig vs 7-endo-trig 100 : 0 7-exo-trig vs 8-endo-trig

adical eactions Intramolecular eactions!!! regiochemistry 48 : 1 >200 : 1 2 : 3 1 : 100

Interlude Baldwin s ules!!! 5-exo-trig size of forming ring where e- end up nature of bond to which u adds where electrons end up! exo = outside newly formed ring! endo = inside newly formed ring! nature of bond to which u adds! tet = tetrahedral (sp 3 )! trig = trigonal (sp 2 )! dig = digonal (sp)!

Interlude Alabugin Chem. ev. 2011, 11, 6513. Baldwin s ules!! boxed structures are favored

adical eactions stereochemical models Intramolecular eactions!!! stereochemistry 5-exo 6-endo 65 : 35 25 : 75 83 : 17 27 : 73

adical eactions Intramolecular eactions!!! vinyl radicals - more reactive than saturated counterparts than 1000x faster - low inversion barrier 2 C C 2 2 C C 2 2 C C 2 Bu 3 Sn Bu 3 Sn Br AIB, Δ AIB, Δ Br

adical eactions Intramolecular eactions!!! vinyl radicals Br LDA Br Br Bu 3 Sn, AIB Ph, hν 80% 70% 2 Pd/C * 85 : 15 norseychellene seychellene Stork Tetrahedron Lett. 1985, 26, 5927.

adical eactions Intramolecular eactions!!! TBS examples IS Et Et TBS I C 5 11 TMS Bu 3 Sn (cat) ab 3 C, tbu Et TBS TBS Et Bu 3 Sn (cat) C C Et Et Et TBS C 1. DIBAL 2. (Et) 2 P C 5 11 TBS 3 steps C 5 11 1. 140 C 2. Pd(Ac) 2 58% TBS (3 steps) TMS C 5 11 TBS prostaglandin F 2α

adical eactions Intramolecular eactions!!! examples I Bu 3 Sn AIB, Δ 80% hirsutene 5-exo-trig 5-exo-dig

adical eactions Intramolecular eactions!!! examples SPh Ts SPh Ts SPh Br Ts Bu 3 Sn AIB, Δ 5-exo-trig 6-endo-trig 30% Ts SPh Ts SPh -PhS Ts (-)-morphine Parker J. Am. Chem. Soc. 1992, 114, 9688

adical eactions Intramolecular eactions!!! tethered reaction processes Si Br Cl imidazole Si Bu 3 Sn AIB, Δ Si Br Bu 4 F 2 S 4 2 2 Si Tamao oxidation

adical eactions Intramolecular eactions!!! tethered reaction processes

adical eactions SmI 2 Promoted eductive Coupling!!! radical cyclization / nucleophile attack X SmI 2 Sm III SmI 2 E E then I Ph Ph SmI 2 (2 equiv) TF-MPA 89% I ipr ipr SmI 2 (2 equiv) TF-MPA 55% - other electrophiles include: I 2, PhSSPh, PhSeSePh, Bu 3 SnI, PhC=

adical eactions SmI 2 Promoted eductive Coupling!!! reductive addition of carbonyls ' SmI 2 (2 equiv) ipr ' SmI 2 SmI 2 ; SmIII ' III Sm ' ketyl - for intermolecular reactions, must be an electron withdrawing group Ph C 2 2 SmI 2, ipr TF-MPA 78% Ph

adical eactions e C - 2 C E 2 SmI 2 Promoted eductive Coupling!!! n n n E reductive addition of carbonyls 2 SmI 2, tbu 2 SmI 2, tbu TF-MPA n TF-MPA 86% (n = 1) 91% (n = 2) dr = 150 : 1 dr = 36 : 1 C 2 2 SmI 2, tbu TF-MPA then C 2 2 SmI 2, tbu TF-MPA; then 2 C= 2 2 73% 73% 2 SmI 2, tbu E = PhC TF-MPA E = 2 83% 69% Ph

adical eactions SmI 2 Promoted eductive Coupling!!! reductive addition of carbonyls Et 2 SmI 2 TF-tBu 75% C 2 Et 2 SmI 2 TF-tBu 87% Et SmI 2 (2 equiv) TF-MPA C 2 Et 79%

adical eactions SmI 2 Promoted eductive Coupling!!! basis for selectivity SmI 2 Sm III e- E E ' Et SmI 2 III Sm ' Et III Sm ' Et e- E E ' Et

adical eactions SmI 2 Promoted eductive Coupling!!! examples SmI 2 TF-MPA 69% pts acetone III Sm III Sm coriolin Curran J. Am. Chem. Soc. 1998, 110, 5064

adical eactions SmI 2 Promoted eductive Coupling!!! examples SmI 2, tbu TF-MPA 63% paeonilactone B Sm III Sm III Sm III Kilburn J. Chem Soc., Perkin Trans 1 2001 487.

adical eactions SmI 2 Promoted eductive Coupling!!! examples

adical eactions 1. Et 3 2. PhSeBr, PBu 3 SePh Acyl adicals!!! general features Bu 3 Sn X AIB or hν

adical eactions Barton McCombie eaction!!! C 3 C 3 Br BDE ~ 90 kcak/mol ~ 68 kcal/mol ' S " ' ' C 3 I ~ 53 kcal/mol " = Ph, S,, 1. a 2. S=C=S 3. I Bu 3 Sn (1 equiv) AIB (cat), Δ S S Barton J. Chem. Soc. Perkin Trans 1 1975, 1574. Barton, Motherwell Pure Appl. Chem. 1981, 51, 15. Tatsuta J. Am. Chem. Soc. 1979, 101, 6110.

adical eactions Barton McCombie eaction!!! mechanism C C Δ 2 C S C C S ' S SnBu 3 Bu 3 Sn Bu 3 Sn ' S driving force formation of C= (190 kcal/mol) vs C=S (137 kcal/mol) ' Bu 3 Sn ' S SnBu 3 S

adical eactions Barton McCombie eaction!!! Im S Im S Bu 3 Sn AIB, Δ Barton J. Chem. Soc. Perkin Trans 1 1977, 1718 1. a 2. S=C=S 3. I S S S S Bu 3 Sn AIB, Δ S Im Im Bu 3 Sn AIB, Δ S

adical eactions Barton McCombie eaction!!! examples 1. a, CS 2, I, imid 2. Bu 3 Sn, AIB, Δ 68%

adical eactions eductive Decarboxylation!!! general features 1. SCl 2 2. S S AIB, Δ or hν C 2 S radical traps: Bu 3 Sn 2 then DMS or P() 3 X CX 3 (X = Br, I PhS-SPh SPh S CCl 4 Cl

adical eactions eductive Decarboxylation!!! mechanism - cleavage can also be initiated thermally or with light Derek Barton: obel Prize 1969 For their contributions to the development of the concept of conformation and its application in chemistry. Shared Prize with assel http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1969/barton-bio.html

adical eactions eductive Decarboxylation!!! examples Boc Boc tbu 1. a 2. 2-thiopyridine--oxide, EDC then tbus, hν 52% Boc tbu S Boc tbu physostigmine S Cl Ac tbus, DMAP, Δ 82% Ac