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

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1 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 according to the degree of nitrogen substitution: 1 ( 2 ), 2 ( 2 ), 3 ( 3 ) and 4 ( 4 ) 2 3 alkylamines arylamines primary (1 ) amines secondary (2 ) amines tertiary (3 ) amines quarternary (4 ) ammonium ion ote: Although the terminology is the same, this classification of amines is different from that of alcohols : Structure and bonding. The nitrogen of alkylamines is sp 3 hybridized and tetrahedral. The nitrogen of arylamines (aniline) is slightly flatten, reflecting resonance interactions with the aromatic ring

2 In principle an amine with three different substituents on the nitrogen is chiral with the lone pair of electrons being the fourth substituent; however, for most amines the pyramidal inversion of nitrogen is a racemization mechanism. The barrier to nitrogen inversion is about 25 KJ/mol (very rapid at room temperature). 22.3: Physical Properties. (please read) 22.4: Basicity of Amines. The basicity is reflective of and is expressed as the pk a s of the conjugate acid. The conjugate base of a weak acid is a strong base: igher pk a = weaker acid = stronger conjugate base The conjugate base of a strong acid is a weak base Lower pk a = stronger acid = weaker conjugate base 205 Table 22.1 (p. 915): pk a values of ammonium ions Alkyl ammonium ions, 3 X -, have pka values in the range of (ammonium ion, 4 X -, has a pk a ~ 9.3) The ammonium ions of aryl amines and heterocyclic aromatic amines are considerably more acidic than alkyl amines (pk a < 5). The nitrogen lone pair is less basic if it is in an sp 2 hybridized orbital (versus an sp 3 ) 4 pk a = 9.3 ( 3 2 ) ( 3 2 ) ( 3 2 ) pk a =

3 Arylamines are much less basic than alkylamines. The lone pair of electrons on the nitrogen of aniline are conjugated to the π-electrons of the aromatic ring and are therefore less available for acid-base chemistry. Protonation disrupts the conjugation. Substitutents can greatly influence the basicity of the aniline. The effect is dependent upon the nature and position of the substitutent Electron-donating substituents (- 3, -, - 3 ) make the substituted aniline more basic than aniline itself (the pk a of the anilinium ion is higher than 4.6) Electron-withdrawing substituents (-l, - 2 ) make the substituted aniline less basic than aniline itself (the pka of the anilinium ion is lower than 4.6) Y 3 2 Y 2 3 Y= - 2 pk a = pk a = pk a = pk a = 4.6 -l pk a = 4.0 -F 3 pk a = pk a = pk a = 1.0 less acidic (more basic) more acidic (less basic)

4 22.5: 4 Salts as Phase-Transfer atalysts (please reads) 22.6: eactions That Lead to Amines: A eview and Preview Formation of - bonds: a. ucleophilic substitution with azide ion (h. 8.1, 8.11) S 2 [] 2 X amine b. itration of arenes (h. 12.3) 3 2 [] 2 2 S 4 1 arylamine c. ucleophilic ring opening of epoxides with 3 (h ) 2 S d. eaction of amines with ketones and aldehydes (h ) 2 [] ketone or aldehyde e. ucleophilic substitution of α-halo acids with 3 (h ) ' Br S ' 2 f. ucleophilic acyl substitution (h. 20.4, 20.5, 20.11) ' 2 ' l 2 2 [] '

5 22.7: Preparation of Amines by Alkylation of Ammonia Ammonia and other alkylamines are good nucleophiles and react with 1 and 2 alkyl halides or tosylates via an S 2 reaction yielding alkyl amines. 1, 2, and 3 amines all have similar reactivity; the initially formed monoalkylation product can undergo further reaction to yield a mixture of alkylated products : The Gabriel Synthesis of Primary Alkylamines. reaction of potassium phthalimide with alkyl halides or tosylates via an S 2 reaction. The resulting -susbtituted phthalimide can be hydrolyzed with acid or base to a 1 amine. The Gabriel amine synthesis is a general method for the prepartion of 1 alkylamines (but not arylamines)

6 22.9: Preparation of Amines by eduction. Alkyl azides, nitriles, amides, and nitroarene can be reduced to the corresponding amines. LiAl 4 reduces alkyl azides to 1 amines LiAl 4, 2 X S 2 ether then 2 1 amine LiAl 4 reduces nitriles to 1 amines LiAl 4, 2 X S 2 ether then 2 1 amine LiAl 4 reduces amides to 1, 2 or 3 amines l 2 3 LiAl 4, 1 2 ether then itroarenes are reduced to anilines 3 2 2, Pd/ 2 2 S 4 -or- Fe, l 1 arylamine 22.10: eduction Amination. Imines and iminium ions are easily reduced to amines / Pd/ 2 1 amine 3-phenyl-2-propanone (P2P) ammonia amphetamine / Pd/ 3 2 amine 1 amine methamphetamine ( 3 ) / Pd/ amine 2 amine

7 Sodium cyanoborohydride, a -B 3 : the cyano ligand makes cyanoborohydride a weak hydride source and it will react with only the most easily reduced functional groups, such as an iminium ion. ab() 3 reduces ketones and aldehydes slowly. eductive amination with ab() 3 is a one-pot reaction 3-2 ab() = ab() : eactions of Amines: A eview and a Preview. eaction of ammonia and 1 amines with aldehyde and ketones to afford imines (w/ loss of 2 ) (h ) ' 2 ' 2 eaction of 2 amines with aldehyde and ketones (w/ an α-proton) to afford an enamine (w/ loss of 2 ) (h ) ' ' ' ' 2 eaction of ammonia, 1, and 2 amines with acid chloride, anhydrides and esters to afford amides. (h. 20.4, 20.5, 20.11) X ' ' ' ' -X

8 22.12: eaction of Amines with Alkyl alides. Amines react with alkyl halides and tosylates by nucleophilic substitution (S 2 ). Products from multiple alkylation often results : The offmann Elimination. 1 amine react with excess methyl iodide yield quarternary (4 ) ammonium salts. E2 elimination of the resulting trimethyl ammonium group to give an alkene. 2 ( 3 ) 3 - K o reaction ( 2 - is a very poor leaving group) 3 -I ( 3 ) 3 I - ( 3 ) 3 - K (major) (minor) 217 ofmann elimination gives the less substituted alkene, where E2 elimination of an alkyl halide or tosylate will follow Zaitsev rule to give the more substituted alkene Fig 22.4, p

9 22.14: Electrophilic Aromatic Substitution in Arylamines. The amino group is strongly activating, ortho/para director; however, it is largely incompatible with Friedel-rafts reactions. Electrophilic aromatic substitution of phenyl acetamides (amides of aniline). The acetamide group is still activating and an ortho/para director. 2 ( 3 3 ) 2, pyridine Br Br 2 3 a, 2 Br The acetamides is acts as a protecting group for the arylamine Anilines are so activated that multiple substitution reactions can be a problem. The reactivity of the acetamide is attenuated so that mono substitution is achieved. The acetamide group is compatiable with the Friedel-rafts reactions : itrosation of Alkylamines. (please read) 22.16: itrosation of Arylamines. eaction of aniline with nitrous acid (a 2 ) leads to an aryl diazonium cation, which are value precursors to other functional groups. Aryl diazonium salts react with nucleophiles in a substitution reaction. 2 is one of the best leaving groups. u: u

10 22.17: Synthetic Transformations of Aryl Diazonium Salts. (Fig. 22.5, p. 938) X u 2, 2 ai BF 4 l, ul Br, ubr u() 3 P 2 I F l Br Sandmeyer reaction: promoted by u(i) salts Advantages of the aryl diazonium salt intermediate: 1) Introduces aryl substituents that are not otherwise accessible, such as -, -F, -I, and Advantages of the aryl diazonium salt intermediate: 2) Allows preparation of substituted arenes with substitution patterns that can not be prepared by other means. Synthesis 3,5-dibromotoluene 3 3 Br Br Br

11 Synthesize 2-iodoethylbenzene from benzene: I : Azo oupling. (please read) : Spectroscopic Analysis of Amines. I: - stretches in the range of cm -1 ; this is the same range as an - stretch, but - stretches are less intense. 3 ( 2 ) ( 2 )

12 1 M: itrogen is less deshielding than oxygen. ydrogens on the carbon attached to the amino nitrogen have a typical chemical shift of δ , m , s Ph , t , q , s M: The resonances of carbon attached to a nitrogen of an amine are deshielded about 20 ppm downfield from those of an alkane Mass Spectrum: itrogen rule: small organic compounds with an odd number of nitrogen atoms have an odd mass; compounds with an even number of nitrogen atoms have an 226 even mass 115

13 9 13 [α] D (1, dd, J= 10.7, 4.1) 3.38 (1, dd, J= 10.7, 7.0) (1, m) 2.77 (1, dd, J= 13.3, 5.0) 2.49 (1, dd, J= 13.3, 8.8) (3, br s) (m, 2) (m, 3) 13 M: 138.6, 129.1, 128.5, 126.3, 65.9, 54.2, 40.6 I:

Amines Amines (e.g. RNH 2 ) are organic derivatives of ammonia, NH 3 similar to ammonia

Amines Amines (e.g. RNH 2 ) are organic derivatives of ammonia, NH 3 similar to ammonia 148Exam 2 notes rganic hemistry (e.g. 2 ) are organic derivatives of ammonia, 3 similar to ammonia omenclature: suffix 2 prefix 2 ( 3 ) 2 Types: Primary (1 o ), secondary (2 o ), tertiary (3 o ) or quaternary