Lecture'14:'March'19,'2013

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1 CM'224' 'rganic'chemistry'ii Spring'2013,'Des'Plaines' 'Prof.'Chad'Landrie quinine Lecture'14:'March'19,'2013 Classifica)on,&,omenclature,of,Amines,(24.1) Structure,,Proper)es,,Basicity,,(24.2B24.5) Synthesis,of,Amines,(24.6)

2 CM'224' 'rganic'chemistry'ii Spring'2013,'Des'Plaines' 'Prof.'Chad'Landrie Classificaon,'omenclature'&' Examples'of'Amines 24.1

3 Classifica(on+of+Amines Alkyl Amine: attached to an alkyl group 3 C C3 2 triethylamine dimethylamine cyclohexylamine Aryl Amine: attached to an aryl (aromatic) group 2 aniline diphenylamine rganic Chemistry II (CM 224) Slide 3

4 Classifica(on+of+Amines eterocyclic Amine: in a ring; often aromatic pyridine pyrrole quinoline imidazole indole pyrimidine pyrrolidine piperidine heterocycle is any ring containing two or more atom types rganic Chemistry II (CM 224) Slide 4

5 Classifica(on+of+Amines Alkaloids: aturally occurring compounds containing rder: coleoptera Family: coccinellidae C 5 11 (-)-adalinine A rder: Tetraodontoformes 2 (-)-tetrodotoxin CS 3 C 6 7 B 3' C 6 13 fasicularin Wardrop, D. J., Landrie, C. L. & rtiz, J. A. Total synthesis of the coccinellid alkaloid (+/-)-adalinine utilizing a nitrenium ion cyclization. Synlett (2003). Wardrop, D. J., Zhang, W. M. & Landrie, C. L. Stereoselective nitrenium ion cyclizations: asymmetric synthesis of the (+)-Kishi lactam and an intermediate for the preparation of fasicularin. Tetrahedron Lett. 45, (2004). rganic Chemistry II (CM 224) Slide 5

6 Classifica(on+of+Amines Alkaloids: aturally occurring compounds containing C 3 3 C Ph quinine cocaine coniine rganic Chemistry II (CM 224) Slide 6

7 Classifica(on+of+Amines Alkaloids: aturally occurring compounds containing 3 C (S)-3-(1-methylpyrrolidin-2-yl)pyridine or nicotine rganic Chemistry II (CM 224) Slide 7

8 Classifica(on+of+Amines:+Subs(tu(on Unlike alcohols, amine substitution is determined by the number of Cs directly attached to. 2 3 C C 3 3 C C 3 2º alcohol 1º amine C3 F 2º amine 3º amine quaternary ammonium salt (tetrabutyl ammonium fluoride, TBAF) rganic Chemistry II (CM 224) Slide 8

9 omenclature 1. Primary Amines 3 C functional class name: add -amine to alkyl group name alkyl group as a substituent (-yl) commonly used when amino group is at locant 1 with no branching ethylamine butyl-2-amine 3-methylbutylamine substitutive name: add -amine to alkane parent (drop -e) name alkyl group as a substituent (-yl) common for complex alkyl groups ethanamine 2-butanamine 3-methylbutanamine rganic Chemistry II (CM 224) Slide 9

10 omenclature 2. 1º Amines with more than one functional group aminobutanoic acid 2,4-diaminophenol 4-(methylamino)pentan-2-one aminopentan-2-ol 2,3-diaminopropan-1-ol name -R2 group as -amino substituent amines have lower priority than alochols rganic Chemistry II (CM 224) Slide 10

11 omenclature 3. Symmetrical 2º and 3º amines diphenylamine triethylamine diisopropylamine use use functional class name (-ylamine) add replicating prefix di- or tri- rganic Chemistry II (CM 224) Slide 11

12 omenclature 4. Unsymmetrical 2º and 3º amines,-diethylpropan-1-amine or,-diethylpropylamine -ethyl--methylcyclohexanamine or -ethyl--methylcylohexylamine name as -substituted primary amines alkyl group with longest chain is parent rganic Chemistry II (CM 224) Slide 12

13 CM'224' 'rganic'chemistry'ii Spring'2013,'Des'Plaines' 'Prof.'Chad'Landrie Structure'and'Properes 24.2

14 ybridiza(on and C are sp3- hybridized in methyl amine electron lone-pair on is in a sp3 orbital site of protonation electron density concentrated at location of electron lone-pair s on, relatively acidic (less than alcohols though) rganic Chemistry II (CM 224) Slide 14

15 Chirality+Centers+ther+Than+Carbon Since nitrogen undergoes rapid pyramidal inversion, it is not considered a chirality center. The energy barrier to inversion is large enough for phosphines and sulfoxides, that they are considered chirality centers. Ea (phospine) ~ 132 kcal/mol Ea (sulfoxide) ~ 45 kcal/mol Ea (amines) ~ 24 kcal/mol rganic Chemistry II (CM 224) Slide 15

16 ybridiza(on methylamine aniline formamide increased resonance with adjacent π-systems increases sp2-character of as sp2-character increases, bisector angle increases from 125º to 180º (flat) rganic Chemistry II (CM 224) Slide 16

17 Resonance+in+Aryl+Amines no delocalization of lone-pair is sp 3 hybridized delocalization of lone-pair is sp 2 hybridized rganic Chemistry II (CM 224) Slide 17

18 Resonance+in+Aryl+Amines actual picture is somewhen in between the resonance structures of aniline show nucleophilic sites of benzene ring in nucleophilic aromatic substitution (ortho-para director) rganic Chemistry II (CM 224) Slide 18

19 Boiling+Point less electronegative than oxygen smaller - dipole than - dipole = weaker -bonding in amines less polar, lower boiling point than alcohols rganic Chemistry II (CM 224) Slide 19

20 Boiling+Point among similar MW amines (similar LDFs); 1º have highest bp more - bonds = more -bonding = higher bp tertiary no -bonding = lowest bp rganic Chemistry II (CM 224) Slide 20

21 CM'224' 'rganic'chemistry'ii Spring'2013,'Des'Plaines' 'Prof.'Chad'Landrie Basicity 24.3B24.5

22 Basicity Amines, while relatively weak bases, are the strongest bases among neutral organic compounds 3 C 2 + C 3 K eq = C 3 + C 3 methylamine acetic acid methylammonium acetate pk a = 4.7 pk a = C 2 + K eq = C 3 + methylamine water methylammonium hydroxide pk a = 15.7 pk a = 10.7 rganic Chemistry II (CM 224) Slide 22

23 Basicity Aryl Amines are Significantly Less Basic + K eq = anilinium ion cyclohexylamine aniline cyclhexylammonium ion pk a = 4.6 pk a = 10.6 strongest acid strongest base weakest base weakest acid the stronger the conjugate acid, the weaker the conjugate base the weaker the conjugate acid, the stronger the conjugate base electron lone-pair conjugated with aromatic ring (resonance) in aniline and thus more delocalized and less available for bond formation electron lone-pair is more localized in cyclohexylamine and thus more available to form bonds to atoms rganic Chemistry II (CM 224) Slide 23

24 Basicity Aryl Amines are Significantly Less Basic 2 aniline diphenylamine triphenylamine pka of conjugate acid more and more conjugated aryl amine = less and less basic rganic Chemistry II (CM 224) Slide 24

25 Basicity+of+Subs(tuted+Arylamines Basicity of Aryl Amines Influenced by Substituents Amine Y pka of conjugate acid Y C3 5.3 CF EDGs increase electron density on inductively or through resonance EWGs decrease electron density on inductively or through resonance rganic Chemistry II (CM 224) Slide 25

26 Basicity Pyridine is Less Basic than Piperidine + K eq = pyridinium ion strongest acid piperidine pk a = 5.2 pk a = 11.2 strongest base pyridine weakest base piperidinium ion weakest acid the stronger the conjugate acid, the weaker the conjugate base the weaker the conjugate acid, the stronger the conjugate base electron lone-pair in a sp2 orbital in pyridine and sp3 in piperidine more s-character in pyridine = more electronegative = holds on to electron lone-pair tighter = not as available for bonding R, pyridinium less stable than pyridine because higher s-character = more electronegative atom, which is less stable with positive charge rganic Chemistry II (CM 224) Slide 26

27 Amidine+Bases R R 2 amidine functional group More acidic compared to: Imidazole (Im) Imidazolium ion pyridinium ion pk a = 7 pk a = 5.2 Et Et Et triethylammonium 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) pk a = 12 pk a = 10.6 amidines are common non-nucleophilic bases (don t participate in S) conjugate acid is stabilized by resonance (more stable acid, stronger base) rganic Chemistry II (CM 224) Slide 27

28 Summary Amine pka of ammonium ion DBU Basicity of Amines is compared by considering the pka of their conjugate acids Increasing Basicity pyrrolidine Et Et Et triethylamine (Et 3 ) Imidazole (Im) pyridine (Py) weaker base: smaller pka for ammonium ion (stronger acid) stronger base: larger pka for ammonium ion (weaker acid) aniline Why is pyrrole such a weak base? (Why is it s conjugate acid so strong)? pyrrole 0.4 rganic Chemistry II (CM 224) Slide 28

29 Carboxylic+Acids+at+Physiological+p 3 C 3 C + + What is the percent dissociation in a 0.15 M aqueous solution of acetic acid buffered at p = 7.0? The pka of acetic acid is If p remains constant (i.e. a buffered solution), use the enderson-asselbach equation. If p is allowed to change, use an ICE table. rganic Chemistry II (CM 224) Slide 29

30 Carboxylic+Acids+at+Physiological+p 3 C 3 C + + What is the percent dissociation in a 0.15 M aqueous solution of acetic acid buffered at p = 7.0? The pka of acetic acid is enderson-asselbalch equation rganic Chemistry II (CM 224) ote: When p=pka, the acid is 50% ionized. Slide 30

31 Carboxylic+Acids+at+Physiological+p 3 C 3 C + + What is the percent dissociation in a 0.15 M aqueous solution of acetic acid buffered at p = 7.0? The pka of acetic acid is At physiological p (7.3), carboxylic acids exist almost entirely as their conjugate bases! 3 C rganic Chemistry II (CM 224) ote: When p=pka, the acid is 50% ionized. Slide 31

32 Amines+at+Physiological+p 3 C 3 3 C What is the percent of ammonium ion in a 0.15 M aqueous solution of methyl amine buffered at p = 7.3? The pka of methyl ammonium is enderson-asselbalch equation rganic Chemistry II (CM 224) Slide 32

33 Amines+at+Physiological+p 3 C 3 3 C What is the percent of ammonium ion in a 0.15 M aqueous solution of methyl amine buffered at p = 7.3? The pka of methyl ammonium is At physiological p (7.3), amines exist almost entirely as their conjugate acids! They are fully protonated. 3 C 3 rganic Chemistry II (CM 224) Slide 33

34 Amino+Acids+Are+ZwiFerions+at+Physiological+p amino acids contain both an amino group and a carboxylic acid group. They are the building blocks for proteins. zwitterions are neutral molecules containing both a positively charged atom and a negatively charged atom amino group fully protonated at p = 7.3 acid group fully deprotonated at p = Ph rganic Chemistry II (CM 224) Slide 34

35 CM'224' 'rganic'chemistry'ii Spring'2013,'Des'Plaines' 'Prof.'Chad'Landrie Solubility'and'Extracon 24.2,&,24.4

36 Solubility Amines with 6 carbon atoms are generally soluble in water. The atom is a -bond acceptor to water. Water insoluble amines can be made soluble by making the solution acidic to obtain the ammonium ion aniline anilinium ion not water soluble water soluble rganic Chemistry II (CM 224) Slide 36

37 Three+Ionizable+Func(onal+Groups+in+Water R deprotonation + R + 2 pk a ~ 4 pk a = 15.7 carboxylic acid (conjugate acid) carboxylate anion (conjugate base) R deprotonation + R + 2 pk a ~ 4 pk a = 15.7 phenol (conjugate acid) phenoxide anion (conjugate base) R 2 amine (conjugate base) protonation + 2 R 3 + pk a ~ 1.7 pk a ~ 9.0 ammonium cation (conjugate acid) 2 rganic Chemistry II (CM 224) Slide 37

38 General+Scheme+for: Base+Extrac(on+of+1:1+Benzoic+Acid/Acetanilide 1. eutralize/ Protonate with 3 M Cl 1. recrystallize from boiling water 2 a 2. Vacuum filter precipitated benzoic acid crude solid: not pure/clean depressed mp possibly discolored 2. vacuum filter pure solid: white crystals sharp mp narrow mp range 2 a Add 3 M a (aq) separate layers C 2 Cl 2 C2Cl2 is denser than water = bottom layer C 2 Cl 2 C 2 Cl 2 evaporate C 2 Cl 2 crude solid: not pure/clean depressed mp possibly discolored C 3 1. recrystallize from boiling water 2. vacuum filter C 3 pure solid: white crystals sharp mp narrow mp range Amides are not bases due to resonance delocalization of lone-pair. They are not protonated! rganic Chemistry II (CM 224) Slide 38

39 Acid+Extrac(on+of+an+Amine 1. eutralize/ Protonate with 3 M Cl 2 purify 2 2 Cl 2. Separate aniline and water layers or discard if unwanted crude liquid: not pure/clean depressed mp possibly discolored 2 2 Add 3 M Cl (aq) Cl separate layers C2 Cl 2 C 2 Cl 2 evaporate C 2 Cl 2 C 1. recrystallize from boiling water C C 2 Cl 2 crude solid: not pure/clean depressed mp possibly discolored 2. vacuum filter pure solid: white crystals sharp mp narrow mp range ften, the amine was used as a base in a reaction and is discarded with the aqueous layer. rganic Chemistry II (CM 224) Slide 39

40 CM'224' 'rganic'chemistry'ii Spring'2013,'Des'Plaines' 'Prof.'Chad'Landrie ext'lecture.'.'. Finish,Ch.,24

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