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18.7  Halogenation of Aldehydes and Ketones

18.7  Halogenation of Aldehydes and Ketones. O. O. H +. R 2 CCR'. R 2 CCR'. H. X. General Reaction. +. +. X 2. H X. X 2 is Cl 2 , Br 2 , or I 2 . Substitution is specific for replacement of  hydrogen.

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18.7  Halogenation of Aldehydes and Ketones

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  1. 18.7 Halogenation ofAldehydes and Ketones

  2. O O H+ R2CCR' R2CCR' H X General Reaction + + X2 HX • X2 is Cl2, Br2, or I2. • Substitution is specific for replacement of hydrogen. • Catalyzed by acids. One of the products is an acid (HX); the reaction is autocatalytic. • Nota free-radical reaction.

  3. O O Cl + HCl + Cl2 Example H2O (61-66%)

  4. O O CH CH H Br Example • Notice that it is the proton on the  carbon that is replaced, not the one on the carbonyl carbon. CHCl3 + HBr + Br2 (80%)

  5. 18.8 Mechanism of  Halogenation ofAldehydes and Ketones

  6. Interpretation no involvement of halogen until after therate-determining step Mechanism of  Halogenation Experimental Facts • specific for replacement of H at the  carbon • equal rates for chlorination, bromination, and iodination • first order in ketone; zero order in halogen

  7. Mechanism of  Halogenation Two stages: • first stage is conversion of aldehyde or ketone to the corresponding enol; is rate-determining • second stage is reaction of enol with halogen; is faster than the first stage

  8. OH O O slow X2 RCH2CR' RCHCR' RCH CR' fast X enol Enol is key intermediate Mechanism of  Halogenation

  9. Mechanism of  Halogenation Two stages: • first stage is conversion of aldehyde or ketone to the corresponding enol; is rate-determining • second stage is reaction of enol with halogen; is faster than the first stage examine second stage now

  10. •• •• OH OH •• •• R2C R2C + CR' CR' + Br •• •• •• •• •• Br Br •• •• •• •• – •• Br •• •• •• + OH •• R2C CR' Br •• •• •• Reaction of enol with Br2 • carbocation is stabilized by electron release from oxygen

  11. – •• •• Br Br H •• •• •• •• •• •• + H O O •• R2C R2C CR' CR' Br Br •• •• •• •• •• •• Loss of proton from oxygen completes the process ••

  12. 18.9The Haloform Reaction

  13. The Haloform Reaction • Under basic conditions, halogenation of a methyl ketone often leads to carbon-carbon bond cleavage. • Such cleavage is called the haloform reaction because chloroform, bromoform, or iodoform is one of the products.

  14. O (CH3)3CCCH3 O (CH3)3CCONa O (CH3)3CCOH Example Br2, NaOH, H2O + CHBr3 H+ (71-74%)

  15. O O O ArCCH3 (CH3)3CCCH3 RCH2CCH3 The Haloform Reaction • The haloform reaction is sometimes used as a method for preparing carboxylic acids, but works well only when a single enolate can form. yes yes no

  16. O O RCCH3 RCCX3 O O RCCH2X RCCHX2 Mechanism • First stage is substitution of all available hydrogens by halogen X2, HO– X2, HO– X2, HO–

  17. – •• •• O O •• •• •• •• – CX3 CX3 HO RC RC •• •• HO •• •• •• •• O O •• •• – – •• •• + + HCX3 CX3 RC RC O OH •• •• •• •• Mechanism • Formation of the trihalomethyl ketone is followed by its hydroxide-induced cleavage +

  18. 18.10Some Chemical and StereochemicalConsequences of Enolization

  19. O H H H H O D D D D Hydrogen-Deuterium Exchange + 4D2O KOD, heat + 4DOH

  20. •• O •• – H H •• OD •• H H •• – •• O •• •• H H •• + HOD H •• Mechanism +

  21. •• O •• – H D •• + OD •• H H •• – •• O •• •• H •• H OD D H •• Mechanism

  22. H O H3C CC6H5 C CH3CH2 Stereochemical Consequences of Enolization H3O+ 50% R50% S 50% R50% S 100% R H2O, HO–

  23. H H3C OH O H3C C CC6H5 CC6H5 C CH3CH2 CH3CH2 Enol is achiral R

  24. O C H3C OH C CC6H5 H CH3CH2 O H3C CC6H5 C CH3CH2 Enol is achiral H3C H CC6H5 S 50% CH3CH2 50% R

  25. H O H3C CC6H5 C CH3CH2 Results of Rate Studies • Equal rates for:racemizationH-D exchangebrominationiodination • Enol is intermediate and its formation is rate-determining

  26. 18.11Effects of Conjugation in -Unsaturated Aldehydes and Ketones

  27. Relative Stability • aldehydes and ketones that contain a carbon-carbon double bond are more stable when the double bond is conjugated with the carbonyl group than when it is not • compounds of this type are referred to as , unsaturated aldehydes and ketones

  28. O    CH3CH CHCH2CCH3 (17%) K = 4.8 O (83%) CHCCH3 CH3CH2CH    Relative Stability

  29. O H2C CHCH Acrolein

  30. O H2C CHCH Acrolein

  31. O H2C CHCH Acrolein

  32. O H2C CHCH Acrolein

  33. – •• •• O O C C •• •• •• C C C C + – •• O C •• •• C C + Resonance Description

  34. •• O C •• C C  Properties • -Unsaturated aldehydes and ketones are more polar than simple aldehydes and ketones. • -Unsaturated aldehydes and ketones contain two possible sites for nucleophiles to attack • carbonyl carbon • -carbon

  35. O O  = 2.7 D  = 3.7 D Dipole Moments – – • greater separation of positive and negative charge + + + Butanal trans-2-Butenal

  36. 18.12Conjugate Addition to -Unsaturated Carbonyl Compounds

  37. Nucleophilic Addition to -Unsaturated Aldehydes and Ketones • 1,2-addition (direct addition) • nucleophile attacks carbon of C=O • 1,4-addition (conjugate addition) • nucleophile attacks -carbon

  38. Kinetic versus Thermodynamic Control • attack is faster at C=O • attack at -carbon gives the more stable product

  39. O C C C H Y H O Y C C C + • formed faster • major product under conditions of kinetic control (i.e. when addition is not readily reversible) 1,2-addition

  40. O C C C H Y H O C Y C C + • enol • goes to keto form under reaction conditions 1,4-addition

  41. O C C C H Y O C Y H C C + • keto form is isolated product of 1,4-addition • is more stable than 1,2-addition product 1,4-addition

  42. O C C C H Y O H O C Y C Y H C C C C + 1,2-addition 1,4-addition C=O is stronger than C=C

  43. 1,2-Addition • observed with strongly basic nucleophiles • Grignard reagents • LiAlH4 • NaBH4 • Sodium acetylide • strongly basic nucleophiles add irreversibly

  44. O + CHCH CH3CH HC CMgBr OH CHCHC CH3CH CH (84%) Example 1. THF2. H3O+

  45. 1,4-Addition • observed with weakly basic nucleophiles • cyanide ion (CN–) • thiolate ions (RS–) • ammonia and amines • azide ion (N3–) • weakly basic nucleophiles add reversibly

  46. •• via O O •• – CH C6H5CH CC6H5 C6H5CH CHCC6H5 •• CN ethanol,acetic acid KCN •• – O O •• •• C6H5CHCH2CC6H5 CC6H5 C6H5CH CH CN CN Example (93-96%)

  47. •• O •• via – •• CH3 SCH2C6H5 CH3 •• – O O •• •• CH3 CH3 SCH2C6H5 SCH2C6H5 Example O C6H5CH2SH HO–, H2O (58%)

  48. 18.13Addition of Carbanions to-Unsaturated Carbonyl Compounds:The Michael Reaction

  49. Michael Addition • Stabilized carbanions, such as those derived from -diketones undergo conjugateaddition to ,-unsaturated ketones.

  50. O O CH3 H2C CHCCH3 O O O CH3 CH2CH2CCH3 O Example + KOH, methanol (85%)

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