Chemistry 206 Advanced Organic Chemistry Handout–09A Synthetic & Mechanistic Overview of Electrophilic Halogenation Matthew D. Shair Monday, October 7, 2002 Andy Ratz Evans Group Seminar, May 7, 1992 Schmid, G. H.; Garratt, D.G. The Chemistry of Double Bonded Functional Groups , Wiley, Chichester 1977, pp. 765-789 Dubois, J.E.; Mouvier, G. Bull. Soc. Chim. France 1968 , 765 The rate of addition is increased with increasing substitution on the double bond.Introduction of one bulky substituent (ie. t-Bu) retards the rate slightly.Cis olefins react faster the trans isomers .. . k rel Alkene 1 61705727 547026201700 130,000 1,800,000 CH 2 =CH 2 CH 3 CH=CH 2 n-PrCH=CH 2 i-PrCH=CH 2 t-BuCH=CH 2 (CH 3 ) 2 C=CH 2 cis-CH 3 CH=CHCH 3 trans-CH 3 CH=CHCH 3 (CH 3 ) 2 C=CHCH 3 (CH 3 ) 2 C=C(CH 3 ) 2 Substituent Effects on Bromination Rates . . Chlorination and iodination of olefins have similar kinetics and product stereochemistry to brominations. In synthesis, bromine and iodine have been used interchangebly. Conjugated olefins give a mixture of syn and anti products. The ratio of these products is highly dependent onalkene structure. Stereochemistry of addition to nonconjugated olefins is trans The rate of bromination is first order in alkene, but the order of bromine depends on how the reaction is run .. General Aspects of Electrophilic Bromination 09A-Bromination 01 10/4/00 2:40 PM δ ? δ + . de la Mare, P. B. D.; Bolton, R. Electrophilic Additions to Unsaturated Systems , 2nd Ed., Elsevier Publishing, New York 1982 Yates, K. J. Org. Chem. , 1973 38 , 2460 .. . .. Reactions that are third order in Br 2 have been proposed, but there is no conclusive evidence for this Iodination reactions have been shown to react with overall fourth order kinetics III. Higher order reactions Rate Law: -d[Br 2 ]/dt = k[Olefin][Br 2 ] 2 Reactions run with higher concentrations of Br 2 in aprotic solvents Proposed that second molecule of Br 2 catalyzes the heterolytic bond cleavage in rate determining step which forms Br 3 - . Alternatively, one Br 2 may be acting as the nucleophile and one acts as an electrophile (not as likely). II. Third Order Reactions . Rate Law: -d[Br 2 ]/dt = k[Olefin][Br 2 ] Reactions run with dilute bromine in water or alcohol solventsNo relationship between rate and product composition so the product forming stages follow the rate determining stepThere is a large solvent effect consistent with a highly polarized transition state, and a large solvent deuterium isotope effect k(Br 2 , MeOH)/k(Br 2 , MeOD) = 1.4. . . . I. Second order reactions: Kinetics of Electrophilic Bromination Br Br H O R 09A-Bromination 02 10/4/00 4:34 PM Schmid, G. H. The Chemistry of Double Bonded Functional Groups , Wiley, New York 1990, p.699 . . IR, Raman, and UV studies show the presence of a donor acceptor complexThe rate determining step is the disappearance of this donor-acceptor complex. Steps A and B have been considered irreversible in most kinetic analyses.The σ -complex may be a bromonium ion or bromocarbocations depending on the olefin used. . Products Products BSlow ASlow Br - + + Br -. HOR σ -complex σ -complex charge transfer complex ( π -complex) Overall Reaction Mechanism Br 2 Br Br Br Br Br 3 – Br 3 – Br 2 Br 2 Second Order Kinetics Third Order Kinetics 09A-Bromination 03 10/4/00 5:23 PM Olah, G. A. J. Am. Chem. Soc. 1967 , 89 , 4744 Olah, G. A. J. Am. Chem. Soc. 1968 , 90 , 947 Evidence for Cyclic Bromonium Ions I. NMR Studies i. Symmetrical Case: SbF 5 SO 2 + + Not observed + SbF 5 SO 2 + Dichloro and diiodo compounds behave much like the dibromideTwo distinct types of methyl groups for the fluoro compound indicates that a β -fluoro carbocation is the major intermediate for this compound. The fluorine resonance is alsoindicative of an open carbocation.The bromo compound exhibits only one methyl resonance even when cooled to -120 ° C. .. . Me F Me F Me Me Me Me F Me Me F Me Me Br Me Br Me MeMe Br Me Me Br 09A-Bromonium 04 10/5/00 6:46 PM CH 3 CH 2 CH 3 CH 2 Olah, G. A. J. Am. Chem. Soc. 1969 , 91 , 5801 Olah, G. A. J. Am. Chem. Soc. 1974 , 96 , 3565 . Open chlorocarbonium ion has long range coupling thru sp 2 cationic center No long range coupling observed in the bromonium case implies a cyclic bridged intermediateNo 13 C data is given for the chloro-version 13 C data (variable temp.) for bromonium gives evidence for an equilibrium process. This low temp. study suggests that the intermediate is mainly a static bridged ion in equilibrium with a small amount of β -haloalkyl carbonium ion. Evidence for Cyclic Bromonium Ions I. NMR Studies (cont'd) ii. Unsymmetrical Case: .. . + SbF 5 SO 2 + Not observed SbF 5 SO 2 + + Me Cl Me Cl Me Me Me Me Cl H H H H Cl Me Me Br H Br H Br Me Me Me Me Br H H 09A-Bromonium 05 10/4/00 2:44 PM 2 eq Br 2 -2 eq Br 2 II. Crystal Structure of Adamantylideneadamantane Bromonium Ion Evidence for Cyclic Bromonium Ions C-Br bond lengths are slightly longer than in normal alkyl bromides: 2.116 ? and 2.194 ? vs. 1.93-2.04 ? .C-C bond is 1.497 ? which is shorter than sp 3 hybridized C-C bond (1.54 ?) but longer than C=C (1.336 ? in starting material).Br 3 - counterion is linear but lengths are not symmetrical. Br-1 is interacting with Br-3 which causes an asymmetry in the molecule (accounts for different C-Br-1 bond lengths).Br-1 and Br-3 are within van der Waals distance (3.097 ? vs. 3.7 ? for van der Waals). Slebocka-Tilk, H.; Ball, R. G.; Brown, R. S. JACS 1985 , 107 . 4504 C C Br Br 3 – Br-1 Br-4 Br-2 Br-3 X-ray structure 2.116 ? 2.194 ? 1.497 ? 09A-Bromonium 06 10/4/00 3:01 PM Brown, R. S.; Gedye, R.; Slebocka-Tilk, H. J. Am. Chem. Soc. 1984 , 106 , 4515 . Observed products have exclusively trans stereochemistryThe extent of reversibility most likely depends on the structure of the olefin used . Proposed Mechanism: Crossover products Br 2 + Br - + H : 94.7 4.1 0.35 0.7 75 ° C KBr, AcOH 1.3 5.2 2.4 91.7 KBr, AcOH 75 ° C % Products Reaction Reversibility in the Formation of a Bromonium Ion Br Br Br Br Br Br OBs OAc Br OBs OAc Br OBs Br Br + S OO Br = Bs 09A-Bromonium 07 10/4/00 4:09 PM Reversibility cont'd 12 3 HBr (g)RT Run Solvent 12 3 1234 * (CH 2 Cl) 2 CHCl 3 CCl 4 CHCl 3 254044 162439 362115 <1 50 Products 2 and 3 were quantitatively recovered when resubjected to the reaction conditions Used the COCl protecting group on Nitrogen to prevent the stabilization of a benzylic carbocation.This was used in reactions involving the oxirane derivative of 1 where exclusive anti addition products were formed. No ring restriction to acridane derivatives were found.Concerted elimination forming H 2 O and Br 2 have been excluded due to the reactions involving BF 3 OEt 2 which cannot react thru a bromide assisted concerted elimination. A concerted elimination was also ruled out in analogous reactions of HBr and 2-bromo-1,2-diphenyl-ethanol. When 3 was dissolved in CH 3 CN and cis-stilbene was added in the absence of acid, the products obtained were 2 and dibromostilbene. .. .. * Reaction run with BF 3 OEt 2 instead of HBr and resorcinol added to scavenge Bromine produced. Bellucci, G.; Bianchini, R. J. Am. Chem. Soc. 1988 , 110 , 546 Bellucci, G.; Chiappe, C. J. Am. Chem. Soc. 1987 , 109 , 515 N OH Br O Cl Cl O NN Br Br O Cl 09A-Bromonium 08 10/4/00 4:10 PM k y k x k Br Bromonium vs ββββ -Bromocarbocation Three reaction pathways for stilbenes: The mode of reaction is strongly affected by solvent (polar sovents tend to accelerate the carbonium pathways while nonpolar solvents the bromonium pathway is predominent).The X and Y substiuents also greatly affect the reaction pathway (electron donating substituents favor k x and k y while electron withdrawing substituents favor k Br ). .. Schmid, G. H.; Garratt, D.G. The Chemistry of Double Bonded Functional Groups , Wiley, Chichester 1977, pp. 775-779 Bellucci, G., et al. J. Am. Chem. Soc. 1991 , 113 , 8012 X Y Y X X Y Y acceptor do nor X acce ptor X Y donor Br 2 Br + H H Br Br 09A-Bromonium 09 10/4/00 4:13 PM Bellucci, G., et al. J. Am. Chem. Soc. 1991 , 113 , 8012 .. .. Only 4d was anti stereoselective which implies reaction thru an apparently symmetrically bridged bromonium ionReactions 4a and 5a give the same ratio of products. This implies that they are reacting thru essentially the β -bromo carbonium ion. In the case of 5d, "the steric strain of a cis bromonium ion must be so high that isomerization to the trans ion occursdespite the destabilization of the open carbonium ion".Open or weakly bridged ions are attacked preferentially at carbon than are fully bridged bromonium ions which maybe attacked at bromine (reversibility!). This gives evidence for a mechanistic shift of the rate determining step from ionization to the product forming step. Br 2 , RT (CH 2 Cl) 2 Br 2 , RT (CH 2 Cl) 2 Reactions with Cis and Trans Stilbenes 4 7 6 5 7 6 4 0.060.100.152.10 4/(6+7) Entry 6 7 abcd HH CF 3 CF 3 CH 3 HH CF 3 685573 >95 3245275 302815 2 707285 >98 CH 3 HH CF 3 HH CF 3 CF 3 abcd 7 6 Y X Entry H H Y X X Y H H Br Br Br Br H H X Y Y X H H Br Br Br Br H H Y X X Y H H X HH Y 09A-Bromonium 10 10/4/00 4:18 PM Marshall, D. R.; Warnhoff, E. W. Can. J. Chem. 1971 , 49 , 885 Br 2 , 0 ° C CCl 4 .. . . All compunds are kinetically controlled addition products as shown by control experiments withHBr. They are not from secondary reactions or isomerizations.Products are not formed via radical chain processes as shown thru the use of radical scavengersCompound 9 is mainly formed thru HBr addition Compound 11 is formed in equal amounts from two separate processes as shown by 14 C labelling experiments. 27.330.731.822.8 1.90.61.31.5 3.11.73.03.2 12.4 9.7 12.113.5 3.01.13.13.6 34.445.536.042.2 16.710.211.4 2.4 Normal (0 ° C) Low Temp (-78 ° C) Radical ScavengerHBr Scavenger 15 14 13 12 11 10 9 Experiment 15 14 13 12 11 10 9 8 Bromonium Induced Rearrangement of Norbornene Br Br Br Br Br Br Br Br Br Br Br Br 09A-Bromonium 11 10/4/00 4:19 PM + + + 13 14 15 11 12 6,2 6,1 2,1 Mechanism of the Rearrangement Marshall, D. R.; Warnhoff, E. W. Can. J. Chem. 1971 , 49 , 885 1 2 3 4 5 6 7 Br + Br Br H Br Br Br Br Br Br Br Br Br Br Br 09A-Bromonium 12 10/4/00 4:20 PM Bartlett, P. A.; Richardson, D.; Myerson, J. Tetrahedron 1984 , 12 , 2317 K= Kinetic Control: 3 eq. I 2 , MeCN, NaHCO 3 , 0 ° C T= Thermodynamic Control: 3 eq. I 2 , MeCN, 0 ° C 69 9280 7868 9781 8377 T: 1 : 20 K: 1 : 20T: 1 : 20 K: 1 : 1.8T: 1 : 1.1 K: 1: 3T: 1: 6 K: 2.3 : 1T: 1 : 15 Selectivity Yield Products Substrate Selectivities in Iodolactonizations HOOC Me Me HOOCHOOC Me Me HOOCHOOC Me Me Me O O I I O OO O I I O O O O I I O OO O O OO O O O I I H II H H H 09A-Bromonium 13 10/4/00 4:20 PM Iodolactonization in Synthesis of Monensin 1. O 3 , -78 ° C, acetone Jones reagent -78 ° C 2. Pb(OAc) 4 , Cu(OAc) 2 C 6 H 6 , 80 ° C 73% 1. KOH, MeOH, H 2 O 2. I 2 , MeCN, -15 ° C 72h, 89 % 1. THF, -20C 2. 10% Pd/C, H 2 , Et 2 O 84% 1. LAH, Et 2 O 2. Me 2 CO, CuSO 4 TsOH3. CrO 3 . C 5 H 5 N . HCl CH 2 Cl 2 80% + DMSO, RT, 18h 70% KI 3 , NaHCO 3 H 2 O, 87% AgO 2 CCF 3 CH 2 Cl 2 , 50% 1. Jones Reagent2. 2-PyrSH, (COCl) 2 Et 3 N Collum, D. B.; McDonald, J. H.; Still, W. C. J. Am. Chem. Soc. 1980 , 102, 2118 Me COOBz O COOBz Me O I Me H H Me HO O O O - K + O O CHO Me Ph 3 P COOH Me Me Me O O Me Me HOOC Me Me O O O Me I O O O O Me HO H Me Me Me Me O H PyrS Me O O O diastereoselection: 20:1 09A-Bromonium 14 10/4/00 4:22 PM Reaction conditions: I 2 , NaHCO 3 , 0 ° C to RT Substrate Products Yield Selectivity 91 : 998 : 293 : 7 1 : 6 1 : 4 1 : 2.5 949879828781 Selectivities in Iodoetherifications Tamaru, Y.; Hojo, M.; Yoshida, Z. J. Org. Chem. 1987 , 52 , 4062 OH Me HO Ph Me OH OH HO OHOH OH Me Ph OH OH Me PhPh Me OH OH O OH I Me H I OH O H Me OH O O OH Me H PhPh I O OH Me H H Me OH O I H Ph Ph I H I I Ph O OH Me H O Ph OH IMe Me I OH Ph O 09A-Bromonium 15 10/4/00 4:23 PM Wiliams, D. R.; White, F. H. J. Org. Chem. 1987 , 52 , 5067 Synthesis of Citreoviral : 2 3 1. H 2 CCHMgBr, THF, 0 ° C 78%2. MEMCl, i-Pr 2 NEt CH 2 Cl 2 , 82% 85% 1. O 3 , CH 2 Cl 2 , -78 ° C 2. + 1. I 2 , MeCN, NaHCO 3 0 ° C, 80% 2. BzCl, DMAP 83% 1. DBU, o-DCB, ? 2. O 3 , CH 2 Cl 2 , -78 ° C 89% 1. Ph 3 P=CCH 3 COOEt PhH, 80 ° C 93% 2. ZnBr 2 , CH 2 Cl 2 87% 3. DIBAL, CH 2 Cl 2 , -78 ° C 70% MnO 2 , Et 2 O, 68% Me OP h O Me Me Ph O OMEM Me MgBr OBn OH Me MEMO Me Me Me Me Me Me MEMO Me OHOBn O Me Me Me OBz OR Me I Me OR OBz CHO Me Me O O Me Me OH OH Me Me OH CHO Me Me OH OH Me Me O diastereoselection: 9.5 : 1 09A-Bromonium 16 10/4/00 4:24 PM + I 2 , CH 2 Cl 2 , Et 2 O RT, 25% 1. Ph 3 P, THF, RT 2. NaBH 4 , MeOH 90% Synthesis of (+)-Croomine Williams, D. R.; Brown, D.; Benbow, J. W. J. Am. Chem. Soc. 1989 , 111 , 1923 O CHO O COOM e Me Me N 3 Me COOM e NH O O Me H H N Me O O O O Me H H IC O 2 Me Me H N N O O Me H Me O O H H OMe O 09A-Bromonium 17 10/4/00 4:25 PM I 2 , THF pH5 buffer, 0 ° C R 1 R 2 R 3 R 4 Selectivity Yield n-Bu t-Bu MeMe n-Bu Me n-Bun-Bun-Bu MeMe n-Bu i-Pr HH MeMeMe HHHH Me n-Bu HHH HHHHHH Bn TBS Me 99: 01 97 : 0393 : 0788 : 1277 : 2397 : 0390 : 1088 : 1288 : 12 937293667772919985 1. HOAc, Bu 3 B,THF, LiBH 4 , H 2 O 2 2. TIPSCl, DMAP, CH 2 Cl 2 71% I 2 , THF KH 2 PO 4 1. Bu 3 SnH 2. Me 2 C(OMe) 2 TsOH, 67% Cytovaricin Selective Formation of 2-Iodo-1,3-Diols Chamberlin, A. R.; Mulholland, R. Tetrahedron 1984 , 40 , 2297 Evans, D. A.; Kaldor, S. W.; Jones, T. K. J. Am. Chem. Soc. 1990 , 112 , 7001 R 1 R 2 R 3 OR 4 R 4 O R 3 R 2 R 1 OH I X N Me O Me OH OH Me TIPSO Me Me TIPSO Me OH I OH O O Me TIPSO Me Me Me diastereoselection: 96 : 4 09A-Bromonium 18 10/4/00 4:28 PM