ADDITIONS OF AMINES TO CARBONYL GROUPS

1. ADDITIONS OF AMINES TO CARBONYL GROUPS Aldehydes and Ketones

2. MANTRA (Memorization Jingle) Reactions with C=O : Primary amines yield imines Secondary amines yield enamines Tertiary aminesdo not react we will come back to this again and again AMINES: .. .. .. primary secondary tertiary

3. PRIMARY AMINES IMINES

4. Addition-Elimination:The Formation of Imines ketone or aldehyde .. a “carbinolamine” intermediate .. + H primary amine Addition of the amine is followed by a loss of water (elimination). Imines are compounds with a C=N bond G is a primary alkyl group

5. H H-O H H H-O-H + H-O-H + + H-O-H H-O H H Mechanism of Imine Formation weak base addition - acid catalyzed 2 1 acid-catalyzed addition proton exchanges an imine .. + + loss of water (elimination) deprotonation

6. Formation of Simple Imines overall result remove These reactions do not favor the formation of the imine unless: - the product is insoluble (crystallizes or precipitates) or - water is removed to drive the equilibrium

7. Hydrolysis of Simple Imines REVERSAL In an excess of aqueous acid, simple imines hydrolyze back to the aldehyde or ketone and the amine from which they were orginally formed ….. H3O+ Imines that are not soluble, however, are difficult to hydrolyze.

8. CRYSTALLINE IMINES HYDRAZONE AND OXIME DERIVATIVES

9. shown below CRYSTALLINE IMINES There are some special amines that yield insoluble products (imines) that are easy to crystallize ….. .. :NH2OH hydroxylamine semicarbazine .. .. R-NH-NH2 various hydrazine compounds 2,4-dinitrophenyl- hydrazine

10. Formation of Oximes hydroxylamine aldehyde or ketone (usually crystallizes)

11. Formation of Hydrazones a hydrazine aldehyde or ketone

12. insoluble red, orangeoryellow precipitate forms a 2,4-DNP 2,4-Dinitrophenylhydrazones 2,4-dinitrophenylhydrazine 2,4-dinitrophenylhydrazine aldehyde or ketone 2,4-dinitrophenylhydrazone (precipitates)

13. Formation of Semicarbazones semicarbazine semicarbazide aldehyde or ketone a semicarbazone (usually crystallizes)

14. DERIVATIVES CRYSTALLINE IMINES CAN BE USED AS DERIVATIVES A derivative is a solid compound (formed from the original compound) whose melting point can help to identify the original compound. What you will see in the tables of unknowns: semicarbazone 2,4-dinitrophenyl- hydrazone ketones bp mp 2-undecanone 231 12 12263 4-chloroacetophenone 232 12 204236 4-phenyl-2-butanone 235 - 142127

15. BIOLOGICAL REACTIONS

16. Pyridoxyl-5’-phosphate (P-5’-P) Converts amino acids to a-ketoacids, and vice versa. Biologically important in transamination reactions. .. an amino acid + - H2O pyridoxyl-5’-phosphate ( P-5’-P ) continued formation of the imine + first imine

17. :Enz Enz-H converts tautomerism H-Enz + Enz: a-ketoacid first imine H2O + new imine Removing the amino group hydrolysis of the new imine + pyridoxamine

18. TRANSFERRING THE AMINO GROUP a different a-ketoacid pyridoxamine tautomerism hydrolysis of the imine These steps are the reverse of those on the previous slides. a different amino acid

19. SUMMARY TRANSAMINATION ( has NH2 ) ( takes NH2 group ) a-Ketoacid-1 + Amino Acid-1 + pyridoxyl-5’-phosphate pyridoxamine-NH2 ( has NH2 ) ( has NH2 ) ( gives NH2 back ) Amino Acid-2 + a-Ketoacid-2 + pyridoxyl- 5’-phosphate pyridoxamine-NH2 ( has NH2 ) is a different a-ketoacid than

20. SECONDARY AMINES ENAMINES

21. Formation of Enamines b-hydrogen is required secondary amine .. benzene “carbinolamine” generally removed by azeotropic distillation an enamine

22. COMPARISON carbinolamine intermediates PRIMARY AMINES SECONDARY AMINES hydrogen on the adjacent carbon .. .. -H2O -H2O no hydrogen on nitrogen hydrogen on the nitrogen imine enamine When there is no hydrogen on nitrogen, one is lost from carbon.

23. piperidine SOME SECONDARY AMINES FREQUENTLY USED TO FORM ENAMINES pyrrolidine Water must be removed morpholine

24. H H-O-H + H H-O-H + O-H H Enamine Formation MECHANISM continued ….

25. Enamine Formation (cont) MECHANISM + H2O H O-H water must be removed to force the equilibrium H3O+ + enamine

26. Nucleophilic Character of Enamines C nucleophilic at carbon X SN2

27. Reactions of Enamines as Nucleophiles SN2 an iminium salt hydrolysis alkylation

28. Az ALKYLATION OF A KETONE pyrrolidine .. iminium salt .. + H+ enamine H3O+ workup remove water +

29. H H-O-H + O-H H Hydrolysis of Iminium Salts MECHANISM continued ….

30. O-H H Hydrolysis of Iminium Salts MECHANISM

31. SUBSTRATES FOR ENAMINE ALKYLATION (and acylation) alkylation X = Cl, Br, I primary secondary allylic acylation enamine acyl compounds may be used

32. CHLORIDES, BROMIDES AND IODIDES In SN2 reactions you learned the rate sequence R-I > R-Br > R-Cl and that iodides are better substrates than chlorides. This is true. Based on this knowledge ….. many students assume that if acid chlorides are good the acid bromides and iodides must be better. However …… acid bromides and iodides are difficult to prepare, and the iodides are quite unstable ….. you should use the chlorides. They are easily prepared from the acid by: R-COOH + SOCl2

33. Enamine Reactions -- Summary secondary amine alkyl or acyl halide

34. TERTIARY AMINES DO NOT REACT

35. H COMPARISON PRIMARY AMINE You need to lose two H’s, one to form the intermediate, one to eliminate water. loses H from N .. H SECONDARY AMINE H is lost to form intermediate loses H from C TERTIARY AMINE : N-R H is lost R .. : unstable The tertiary amine can’t form the carbinolamine intermediate because it lacks an H on N. reverses N-R + R R no H to lose

36. FORMING RINGS SOME GUIDELINES

37. DILUTE SOLUTION AND EXACT STOICHIOMETRY FAVOR RING FORMATION Problem 16-18 in in your textbook. pH = 5 Excess formaldehyde (>2:1) and a more concentrated solution favor the diimime. Also remember that unstrained 5- and 6-rings form easily, other sizes are difficult. 1:1 molar ratio and dilute solution favor the ring formation In dilute solution the molecule is more likely to react internally with itself because encounters with other molecules will be less frequent.

38. HINT ON THE MECHANISM ….. C=N can undergo additions just like C=O Both are polar multiple bonds and both can undergo acid- catalyzed nucleophilic addition. protonation first + CRUCIAL STEP forms ring .. pH 5 mildly acidic ….. see if you can figure out the rest of the mechanism for Problem 16-18 on your own.

39. WITTIG REACTION

40. Ylide - .. + A compound or intermediate with both a positive and a negative charge on adjacent atoms. X Y BOND Betaine or Zwitterion + A compound or intermediate with both a positive and a negative charge, not on adjacent atoms, but in different parts of the molecule. Y MOLECULE - X :

41. Preparation of a Phosphorous Ylide ( WITTIG REAGENT ) precipitates benzene : heat - .. : O-CH3 .. .. ether strong base - + .. Triphenylphosphine ( Ph = C6H5 ) an ylide

42. Resonance in Ylides dp-pp BACKBONDING .. Remember that Phosphorous is a Period III element (d orbitals). P C Backbonding to phosphorous reduces the formal charges and stabilizes the negative charge on carbon. 3d 2p

43. The Wittig Reaction MECHANISM - .. + ylide betaine INSOLUBLE synthesis of an alkene very thermodynamically stable molecule oxaphosphetane (UNSTABLE)

44. + + : ylide - SYNTHESIS OF AN ALKENE - WITTIG REACTION

45. + Br- PhLi .. - + ylide + .. : .. - + triphenylphosphine oxide (insoluble) ANOTHER WITTIG ALKENE SYNTHESIS

46. Muscalure Sex pheromone of the common house fly. Musca Domestica (Z)-9-tricosene Wittig The reaction can be made to give the cis alkene (Z) by correct choice of solvent and temperature, or by the separation of a mixture of cis and trans.