2. Chapter 19 AMINES PROBLEMS 2a,b,e,3a,b,c,6a,c16b,c,17a,c,20b,d21b, 25a,c,e,g,26a,c27b,36a,b,37ab,41c,d,I, 42a,b,c44a,c,g INTRODUCTION Organic derivatives of ammonia 70% of pharmaceuticals contain nitrogen Alkaloids - obtained from plants and have strong biological properties

3. Examples Primary RNH 2 DOPAMINE Parkinson's Disease - inadequate concentration of dopamine Dopamine is a worthless drug since it can't cross blood-brain barrier i.e. can't get in cerebrospinal fluid An amino acid that can cross barrier

4. Examples continued Secondary Amines CONIINE - Hemlock SOCRATES CONIINE - Hemlock SOCRATES methamphetamine speed Tina epinephrine Tertiary Amines HEROIN Morphine

5. Nomenclature Common Names - name radicals attached to nitrogen followed by amine sec-butyldiethylamine 1-aminocyclopentene N-Convention N,N-dimethyl-4-methylaniline

6. IUPAC System ALKANAMINE - Parent longest chain containing amine CH 3 CH 2 CH 2 NHCH 2 CH 2 CH 2 CH 2 CH 3 N-propyl-2-pentanamine 3,4-dichloro-N-methybenzenamine

7. Basicity of amines The greater the availability of the lone pair electrons on nitrogen, the greater the base. Kb = [RNH 3 + ] [OH - ] / RNH 2 In the old days, pK b was a measure of base strength. pK b = - log K b The stronger the base the lower the pK b EFFECTS ON AMINE BASICITY 1. INDUCTIVE EFFECT - ALKYL SUBSTITUTION METHYL GROUP INCREASES ELECTRON DENSITY ON N 3.36 3.28 2 METHYLS ARE BETTER THAN ONE WATCH OUT THREE METHYL GROUPS DECREASES BASICITY pK b = 4.26 - Steric inhibition of solvation of HOH with the NH + of the R3NH + cation.

8. The greater the availability of the lone pair electrons on nitrogen, the greater the base. Kb = [RNH 3 + ] [OH - ] / RNH 2 In the old days, pK b was a measure of base strength. pK b = - log K b The stronger the base the lower the pK b EFFECTS ON AMINE BASICITY 1. INDUCTIVE EFFECT - ALKYL SUBSTITUTION METHYL GROUP INCREASES ELECTRON DENSITY ON N 3.36 3.28 2 METHYLS ARE BETTER THAN ONE WATCH OUT THREE METHYL GROUPS DECREASES BASICITY pK b = 4.26 - Steric inhibition of solvation of HOH with the NH + of the R3NH + cation.

9. 2. RESONANCE EFFECT Base weakening Why?Delocalizes electron pair on N!! pK b = 15 not aromatic Hybridization The greater the % of s character The closer the lone pair is to N The weaker the base sp 2 sp 3 sp 8.75 24 2.88

10. Sections to be omitted 19-7 (salts of amines) 19-8 (amines as PT catalysts) 19-9 (Spectroscopy)

11. Reaction of Amines to be reviewed Reaction with Aldehydes and Ketones - 19-10 Aromatic Substitution of Arylamines 19-11

12. Alkylation of Amines Alkylation of amines by alkyl halides - Only two situations of importance Excess Methyl iodide - all the way to quaternary salt Excess ammonia - stops are monoalkylation stage PhCH 2 Br + excess NH 3 PhCH 2 NH 2 Propyl-NH 2 + ex MeI Propyl-N(Me) 3 +

13. Acylation of Amines AMIDE N-methylbenzamide

14. Mechanism

15. Amines as Leaving Groups Hofmann Elimination HEAT ANTI ELIMINATION - Less stable (less substituted) alkene

16. Stereochemistry H CH 3 H H looking down C2-C3 rotation about C-3 counter clockwise More stable; not Suitable for E-2 Suitable for E-2;less stable

17. Looking down C1-C2 Rotating clockwise about C-2 all suitable for E-2

18. Examples Note: NMe3 has no beta hydrogens thus complicating the E-2 process

19. Another example

20. COPE REACTION N-OXIDE LESS HINDERED BETA HYDROGEN SYN ELIMINATION

21. COPE EXAMPLE Mild conditions

22. Reaction of Primary Amines with HNO 2 Preparation of HNO 2 NaNO 2 + HCl HNO 2 NaCl +

23. Reaction Aliphatic amines RN 2 +R+ Hot carbocation mixture of products

24. Aromatic Primary Amines ArN 2 + 0 - 5 o C stable undergoes SN1 with nucleophiles

25. Examples ArBr ArCl ArF ArCN ArOH ArH

26. Conversion of NO 2 to NH 2 Good way to introduce NH 2 RED = SnCl 2 / HCl

27. Nice Synthesis

28. Another one 1. NaNO3/HCl 2. KI Br 2 / Fe HNO 3 H 2 SO 4 CH 3 I / AlCl 3

29. Synthesis of Amines Reductive Amination NOTE: carbonyl has been reduced and aminated - most general method

30. Examples Primary Amines Could use NH 3 but it is a gas and inconvenient LAH is usual reducing agent

31. Secondary Amines Note: Primary amine is converted to secondary amine.

32. Tertiary Amines iminium salt Very unstabile So reaction is run with reducing presence at all times. This means that there will both product and carbonyl compounds presence. Must use reducing agent that only reduces iminium salt It is: sodium triacetoxyborohydride!!

33. Preparation of Tertiary, Con’t Na(MeCOO) 3 ) 3 BH tertiary amine NOTE: Secondary amine converts to tertiary amine

34. Mechanism of iminium salts -H 2 O

35. EXAMPLE Na(MeCOO) 3 BH

36. Other Ways to Prepare Primary amines REDUCTION OF NITROANILINES - as before REDUCTION OF NITRILES SN2 conditions RCH 2 CH 2 NH essentially replaces halogen with a CH 2 NH 2 group. Increases carbon chain length by one carbon

37. Don’t do problem 27b ch.19 Please do problem 30b, REDUCTION OF AZIDES RCH 2 N 3 RCH 2 NH 2 essentially replaces halogen with an NH 2 group. No increase in carbon chain length NOTE 1-bromopentane to 1-pentanamine - azide but 1-bromopentane to1-hexanamide - CN-