TOPIC 5. AMINES (Chapter 20)

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1 L TPIC 5. AMIES (Chapter 20) BJECTIVES 1. ame aliphatic and aromatic amines 2. Describe the basicity of amines, predict base strength based on structure 3. Recognize nucleophilicity of amines 4. Develop methods to synthesize amines by nucleophilic substitution and reduction of other -containing functional groups

2 R H MECLATURE H R H R' R H S:20.1 Prob: R' R R" 1 amine 2 amine 3 amine alkane alkylamine -alkylalkylamine -alkyl--alkylalkylamine H 2 H 3 C H aniline Br R' R R" Tetraalklyammonium cation R"' Section 20.1B: You do not need to know the names of all of these heterocycles. However, you should be able to describe the structure (hybridization of nitrogen, aromaticity) of these compounds PHYSICAL PRPERTIES, STRUCTURE AD BASICITY F AMIES Structure Trigonal pyramidal nitrogen (sp 3 hybridized). S: If R R R : R R"' R" R' R R" R' Properties Hydrogen bonding (present in 1º and 2º amines) increases the boiling point and solubility in H 2. Compound Boiling point CH 3 CH 2 CH 2 H 2 50 C CH 3 CH 2 HCH 3 34 C (CH 3 ) 3 3 C (CH 3 ) 3 CH -10 C

3 Basicity R 3 + H A R 3 H + A Electron donating alkyl groups: stabilize the conjugate acid increase electron density on nitrogen stronger base Base Conjugate acid pk a (aq. soln) Me 3 Me 3 H 9.7 Me 2 H Me 2 H MeH 2 MeH H 3 H Basicity of Anilines H 2 H 2 H 2 H 3 C H 2

4 ucleophilicity of Anilines H 2 H 3 H 2 S 4 Br 2 R Electron withdrawing groups: destabilize the conjugate acid decrease electron density on nitrogen H 3 CH 3 H 2 pk a of conjugate acid 9 11 weaker base H H 2 0.0

5 Problem What is the order of relative basicity of the following compounds? H 2 H 2 H 2?? Problems ? aming and Preparation

6 L SYTHESIS F AMIES Alkylation of itrogen: Ammonia + alkyl halides Ammonia undergoes polyalkylation S:20.5 Prob: ,29 H 3 R Br Avoiding polyalkylation: HW? What if you want polyalkylation? Gabriel Synthesis: Alkylation of Phthalimide H phthalimide

1. PhMgBr, Et 2 1. H Et 2. H 3 + PBr 3 CH Br a 2 C 3 2.

7 1. PhMgBr, Et 2 1. H Et 2. H 3 + PBr 3 CH Br a 2 C 3 2. KH, EtH, heat H Et 3 H a t-buk, t-buh H 1. H, H 2 2. recrystallize from 2-butanone. 2H C 2 H Fexofenadine: 2-[4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidyl]butyl]phenyl]-2-methyl-propanoic ac Et H PhMgBr H Ph Ph H Br H 3 + H Ph Ph H H C 2H Ph Ph C CH 3 I KtBu C ah H 2 C 2 H 1. ah 2. BuLi C 2 a Br Br Br Li

8 Reduction of itrogen-containing Functional Groups itroarenes H 2,Pt 2 or 1. H, Fe 2. H - Alkyl azides R 1. LiAlH 4 2. H 2 or H 2, Pt itriles R C 1. LiAlH 4 2. H 2 or H 2, Pt ximes H 1. LiAlH 4 2. H 2 or H 2, Pt Amides 1. LiAlH 4 2. H 2 R 2

9 Imines: Reductive amination of aldehydes and ketones R RH 2 H 2, Pt Rearrangements Leading to Amines Hoffman rearrangement (or Hoffman degradation) Br 2 ah H 2 R H 2

10 Curtius Rearrangement 1. a 3 2. Δ R Planning Syntheses of Amines H

11 H Summary of synthetic methods to prepare various amines 1 o amine on 1 o C RBr Gabriel synthesis ; 2. [H] 1. C; 2. [H] RCH 2 [H] RCH H 3 [H] 1 o amine on 2 o C RCR H 3 [H] 3 o amine on 1 o C RCH R 2 H [H] RCR 2 [H] 3 o amine on 2 o C RCR R 2 H [H] α-amino alcohol RCH 1. C; 2. [H] RCR 1. C; 2. [H] 2 o amine on 1 o C RCH RH 2 [H] RCHR [H] 2 o amine on 2 o C RCR RH 2 [H] Aniline Ar- 2 [H] [H] = reduction

12 Problem [Solomons 20.15d,26k] - How would you achieve the following transformations? H H CH 3? H 2 H? Problems 20.24,25,26,29? Preparation

13 L REACTIS F AMIES S:20.5,6,9 Prob:20.30 Review/verview Amines are basic R 3 + H A R 3 H + A Amines are nucleophilic H 3 R Br H 3 R Br H 3 R R H 2 Rings of anilines are nucleophilic H 2

14 Diethylpropion is a stimulant, is marketed as Tenuate for appetite suppression. Propose a synthesis of diethtylpropion from benzene and any other starting materials.? ELIMIATIS IVLVIG AMMIUM CMPUDS Hofmann Elimination S:20.11 Standard (Zaitsev) elimination Br aet 25 o C Hofmann elimination (CH 3 ) 3 H 150 o C 5 95

15 SPECTRSCPIC AALYSIS F AMIES Problem Elemental Analysis: C, 80.5; H, 10.1;, 9.4 MS: M + =149 S Prob: 20.38? IR: 3480, 3395, 3050, 2950, 1622 cm -1 1 H MR: 1.3 (t, 6H), 2.6 (q, 4H), 3.7 (br. s, 2H), 6.8 (t, 1H), 7.1 (d, 2H) Problem The final step in the synthesis of vallium is shown below. How would you prepare the precursor from benzene and any other starting materials. Ph H H Ph H?

16 ? Problems 20.30,38? ac LiAlH 4 X Y Z The 1 H MR spectrum of X gives two signals, a multiplet at δ 7.3 (5H) and a singlet at δ 4.25 (2H). The I H MR spectrum of Y is similar to that of X: multiplet at δ 7.3 (5H), singlet at δ 3.7 (2H). The I H MR spectrum of Z is shown below. L REVIEW: UCLEPHILIC ADDITI-ELIMIATI REACTIS AT ACYL CARBS ucleophilic substitution at sp 2 carbons u + C L C u + L Mechanism: Addition-Elimination u C L C L u C u + L

17 Transformations of acids and acid derivatives R C R C C R R C H R C R' R C R C R' 2 Problem - How would you prepare oxanamide, which is a mild sedative and is anxiolytic. H 2?

18 REVIEW: AMIES Amines are Basic R 3 + H A R 3 H + A Amines are ucleophilic R 3 + R' Br R 3 R' Br What is the correct order of basicity of the following compounds? (more basic > less basic) H H 2 H 2 H CH > 2 > 4 > > 1 > 3 > > 4 > 2 > > 3 > 1 > 4

19 Synthesis R Br R R H 2 R 3 R Br R C R CH 2 H 2 H H 2 R HR H H(R) 2 R CH 2 H(R) 2 Problem The herbicide Propranil is prepared in a five step synthesis from benzene. Identify reagents appropriate for each step.? (a) (b) (c) (d) (e) 2 2 H 2 H

20 Problem - How would you perform the following transformation? CH 3? CH 2 H 2 Problem aproanilide is an herbicide used in rice paddies in Asia. How could this be prepared from naphthol, aniline and any other starting material with three or fewer carbon atoms? H?

21 TPIC 5 (CHAPTER 20) EXAM 4 Types of Questions - omenclature - Predict products (or provide reagents or starting materials to complete a reaction), - Design multistep syntheses - Provide mechanistic rationales Do the problems in the book; they are great examples of the types of problems on the exam! Preparing for Exam 4 - Get up-to-date W! - Work as many problems as possible. Do the problems first, then consult the solutions manual. - Work in groups, discuss chemistry, teach and test each other. - Do the Learning Group Problem at the end of the chapter.

Chapter 22: Amines. Organic derivatives of ammonia, NH 3. Nitrogen atom have a lone pair of electrons, making the amine both basic and nucleophilic

Chapter 22: Amines. Organic derivatives of ammonia, NH 3. Nitrogen atom have a lone pair of electrons, making the amine both basic and nucleophilic hapter 22: Amines. rganic derivatives of ammonia, 3. itrogen atom have a lone pair of electrons, making the amine both basic and nucleophilic 22.1: Amines omenclature. (please read) sp 3 Amines are classified