Chemistry 206 Advanced Organic Chemistry Handout-09A Synthetic Mechanistic Overview of Electrophilic Halogenation andy ratz Evans group seminar, May 7, 1992 Matthew d. shair Monday, October 7. 2002
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
General Aspects of electrophilic bromination a The rate of bromination is first order in alkene, but the order of bromine depends on how the reaction is run a Stereochemistry of addition to nonconjugated olefins is trans Conjugated olefins give a mixture of syn and anti products. The ratio of these products is highly dependent on alkene structure n Chlorination and iodination of olefins have similar kinetics and product stereochemistry to brominations. In synthesis, bromine and iodine have been used interchangebly Substituent Effects on bromination rates CH2=CH CH3CH=CH n-PrCH=cH 70 i-PrCH=CH2 t-BuCH=CH2 (CH3)2C=CH2 CiS-CH3 CH=CHCH3 (CH3)2C=C(cH3)2 1,800,000 The rate of addition is increased with increasing substitution on the double bond a Introduction of one bulky substituent(ie t-Bu) retards the rate slightly Schmid, G. H; Garratt, D.G. The Chemistry of Double Bonded Functional Groups, Wiley, Chichester 1977, pp. 765-789 Bouvier Chim. france 1968. 76 BA-Bromination 01 10/4/00 2: 40 PM
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 . . . Alkene krel 1 61 70 57 27 5470 2620 1700 130,000 1,800,000 CH2=CH2 CH3CH=CH2 n-PrCH=CH2 i-PrCH=CH2 t-BuCH=CH2 (CH3)2C=CH2 cis-CH3CH=CHCH3 trans-CH3CH=CHCH3 (CH3)2C=CHCH3 (CH3)2C=C(CH3)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 on alkene 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
Kinetics of Electrophilic Bromination L. Second order reactions Rate Law: -d[Bradt= k(Olefin Br2] a Reactions run with dilute bromine in water or alcohol solvents No relationship between rate and product composition so the product forming stages follow the rate a There is a large solvent effect tent with a highly polarized transition state, and a large solvent deuterium isotope effect k(Br2, MeOH)/k(Br2, Me Br…H-OR ll. Third Order reactions a Rate li d[Bral/dt= k(Olefin J(Br22 a Reactions run with higher concentrations of Br2 in aprotic solvents Proposed that second molecule of Br2 catalyzes the heterolytic bond cleavage in rate determining step which forms br- Alternatively, one Br2 may be acting as the nucleophile and one acts as an electrophile(not as likely) l. Higher order reactions a Reactions that are third order in Br2 have been proposed, but there is no conclusive evidence for this s lodination reactions have been shown to react with overall fourth order kinetics 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 BA-Bromination 02 10/4/00 4: 34 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 Br2 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[Br2]/dt = k[Olefin][Br2]2 Reactions run with higher concentrations of Br2 in aprotic solvents Proposed that second molecule of Br2 catalyzes the heterolytic bond cleavage in rate determining step which forms Br3-. Alternatively, one Br2 may be acting as the nucleophile and one acts as an electrophile (not as likely). II. Third Order Reactions . Rate Law: -d[Br2]/dt = k[Olefin][Br2] Reactions run with dilute bromine in water or alcohol solvents No relationship between rate and product composition so the product forming stages follow the rate determining step There is a large solvent effect consistent with a highly polarized transition state, and a large solvent deuterium isotope effect k(Br2, MeOH)/k(Br2, MeOD) = 1.4. . . . I. Second order reactions: Kinetics of Electrophilic Bromination Br H OR Br 09A-Bromination 02 10/4/00 4:34 PM
Overall reaction mechanism Br Br HOR ∥Br Products Second order kinetics Br2 Third order Kinetics Br2 Products 3 plex IR, Raman, and Uv studies show the presence of a donor acceptor complex The rate determining step is the disappearance of this donor-acceptor complex. Steps a and b have been considered irreversible in most kinetic analyses The a-complex may be a bromonium ion or bromocarbocations depending on the olefin used Schmid, G. H. The Chemistry of Double Bonded Functional Groups, Wiley, New York 1990, p 699 BA-Bromination 03 10/4/00 5: 23 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 complex The 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 B Slow A Slow Br + + - Br-.HOR σ-complex σ-complex charge transfer complex (π-complex) Overall Reaction Mechanism Br2 Br Br Br Br Br3– Br3– Br2 Br2 Second Order Kinetics Third Order Kinetics 09A-Bromination 03 10/4/00 5:23 PM
Evidence for Cyclic Bromonium lons L. NMR Studies i. Symmetrical Case Me sbF5 Not observed Me SbF5 So2 Dichloro and diiodo compounds behave much like the dibromide Two distinct types of methyl groups for the fluoro compound indicates that a B-fluoro carbocation is the majo ediate for this compound. The fluorine resonance is also indicative of an oper The bromo compound exhibits only one methyl resonance even when cooled to-1200C Olah G.A. J. Am. Chem. Soc. 1967. 89. 4744 PA-Bromonium 04 10/5/00 6: 46 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: SbF5 SO2 + + Not observed + SbF5 SO2 + Dichloro and diiodo compounds behave much like the dibromide Two 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 also indicative 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 Me Me Br Me Me Br 09A-Bromonium 04 10/5/00 6:46 PM
Evidence for Cyclic Bromonium /ons l. NMR Studies(cont'd 5S02 Me Not observed Me SbF5 So2 Open chlorocarbonium ion has long range coupling thru sp" cationic cente No long range coupling observed in the bromonium case implies a cyclic bridged intermediate No13c data is given for the chloro-version a 1c 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 ll amount of B-haloalkyl carbonium ion A J Am. chem. soc. 1969. 91 A J. Am. Chem PA-Bromonium 05 10/4/00 2: 44 PM
CH3 CH2 CH3 CH2 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 sp2 cationic center No long range coupling observed in the bromonium case implies a cyclic bridged intermediate No 13C data is given for the chloro-version 13C 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: . . . + SbF5 SO2 + Not observed SbF5 SO2 + + 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
Evidence for cyclic bromonium lons IL. Crystal Structure of Adamanty lideneadamantane Bromonium lon -2 Br-1 X-ray structure C-Br bond lengths are slightly longer than in normal alkyl 2.116A 2.194A bromides: 2.116 A and 2.194 A Vs 1.93-204A C-C bond is 1.497 A which is shorter than sp hybridized C-C bond(1.54 A)but longer than C=C(1.336 A in starting 1497A material) r3 counterion is linear but lengths are not symmetrical. Br- 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 A vs Slebocka-Tilk.H. Ball R.G. brown.RS JACS 1985. 107 4504 3.7 A for van der Waals) PA-Bromonium 06 10/4/00 3: 01 PM
2 eq Br2 -2 eq Br2 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 Å and 2.194 Å vs. 1.93-2.04 Å . C-C bond is 1.497 Å which is shorter than sp3 hybridized C-C bond (1.54 Å) but longer than C=C (1.336 Å in starting material). Br3- 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 Å vs. 3.7 Å for van der Waals). Slebocka-Tilk, H.; Ball, R. G.; Brown, R. S. JACS 1985, 107. 4504 C C Br Br3– Br-1 Br-4 Br-2 Br-3 X-ray structure 2.116 Å 2.194 Å 1.497 Å 09A-Bromonium 06 10/4/00 3:01 PM
Reversibility in the Formation of a Bromonium lon Products eaction ,OBs 75°C 0.7 035 947 KBr AcOH Proposed Mechanism Crossover products Observed products have exclusively trans stereochemistry The extent of reversibility most likely depends on the structure of the olefin used Brown, R S. Gedye, R; Slebocka-Tilk, H J. Am. Chem. Soc. 1984, 106, 4515 PA-Bromonium 07 10/4/00 4: 09 PM
Brown, R. S.; Gedye, R.; Slebocka-Tilk, H. J. Am. Chem. Soc. 1984, 106, 4515 . Observed products have exclusively trans stereochemistry The extent of reversibility most likely depends on the structure of the olefin used . Proposed Mechanism: Br + Br2 Crossover products - + H : 0.7 0.35 4.1 94.7 75°C KBr, AcOH 91.7 2.4 5.2 1.3 KBr, AcOH 75°C % Products Reaction Reversibility in the Formation of a Bromonium Ion Br Br Br Br Br Br OBs OAc Br OBs Br OAc OBs Br Br+ S O O Br = Bs 09A-Bromonium 07 10/4/00 4:09 PM
Reversibility cont'd HBr (g) Reaction run with BF30Et2 instead of HBr and resorcinol added to scavenge Bromine produced. 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 acridine derivatives were found elimination forming H20 and Br2 have been excluded due to the reactions involving which cannot react thru a bromide assisted concerted elimination. a concerted n was also ruled out in analogous reactions of HBr and 2-bromo-1, 2-dipheny When 3 was dissolved in CH3 CN and cis-stilbene was added in the absence of acid, the products obtained were 2 and dibromostilbene PA-Bromonium 08 10/4/00 4: 10 PM
Reversibility cont'd 1 23 HBr (g) RT Run Solvent 12 3 1 2 3 4 * (CH2Cl)2 CHCl3 CCl4 CHCl3 25 40 44 16 24 39 36 21 15 <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 H2O and Br2 have been excluded due to the reactions involving BF3OEt2 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-diphenylethanol. When 3 was dissolved in CH3CN and cis-stilbene was added in the absence of acid, the products obtained were 2 and dibromostilbene. . . . . * Reaction run with BF3OEt2 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 N N Br Br O Cl 09A-Bromonium 08 10/4/00 4:10 PM
Bromonium vs B-Bromocarbocation Three reaction pathways for stilbenes: Br2 donor a 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 and ky while electron withdrawing substituents favor kBr) 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 PA-Bromonium 09 10/4/00 4: 13 PM
ky kx kBr Bromonium vs β-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 kx and ky while electron withdrawing substituents favor kBr). . . 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 Yacceptor acceptorX donorX Ydonor Br2 Br+ H Br H Br 09A-Bromonium 09 10/4/00 4:13 PM
