Amines (McM chapt 24)

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1 Amines (McM chapt 24) (: alkyl, aryl) - 2 Primary amine ' Secondary amine '' ' Tertiary amine ' ''' '' Quartenary ammonium salts Basic compounds ' '' - ' '' + pka Alkylamines: ca 9-11 Arylamines: ca 4-5 (anilines) (:, alkyl, aryl)

2 Synthesis Known react. from KJM10xx Alkylation (ammonia or amine, phtalimide) (:, alkyl, aryl) - Base - - Base - C 2 C Acidity c.f. 1,3-dicarbonyls eductive amination - 2 [red] Aldehyde ketone ammonia prim amine Imine 2 / i acb 3 etc sec amine - 2 [red] Iminium ion

3 eductions itriles Azides Amides C itrile C LiAl 4 C Azide LiAl 4 C '' ' LiAl 4 Amide, ', '':, alkyl, aryl C '' ' 3 - Aromatic nitro compounds Ar- 2 [red] Ar- 2 ed: 2 / cat SnCl 2, +

4 Synthesis: ew reactions ofmann rearrangement a, Br prim amide C 2 2 Br-Br Br Br C Isocyanate 2 Br Br Acid / base properties amides 2 + pka ca C pka ca -0.5 carbamic acid instable 3 o resonance stab.

5 Curtius rearrangement C 2 3 2, heat + 2 acyl azide acyl azide Cl acyl halide 3 C Isocyanate 2 - C 2-2 Mechanistic. related to ofmann rearrang. 2 Br C Isocyanate 2 - C 2-2 Br

6 eactions of amines (Alkylamines) Alkylamines: Alkylation Acylation / synth of amide ofmann elimination ( ofmann rearrangement) E2 elimination to form alkene E2: mechanism B ' ' ' ' + B + = halogen, () 2 Strong base / bad leaving group C 3 I (excess) Base 2

7 2 C 3 I (excess) Base emoval of less sterically hindered ot necessarily most stable alkene formed 2 C 3 I (excess) 3 C C 3 C3 I Ag C C 3 C3 AgI + 3 C C3 C 3 Much better leaving group than 2 Morphine C 3 Base C 3 3 C C 3 Ph 3 C C 3 Codeine 3 C C 3 -I pka=10.0 pka ca 17 C 3 C 3 -I I C 2 C 3 offman elim C 3 C3 3 C 3 C 3 C

8 eactions of Arylamines (aniline derivatives) 2 Aniline Weak base (pka ca 4.6) ighly Activated for E-fil Ar Subst (o/p) Protect. as amide: Less activated, still o/p ' 3 o/p directing m-directing ucleophilic Aromatic Substitution - Mechanisms S Ar u u u u u S 1 Benzyne S1: Involves radicals (VS: Vicarious ucl. Subst.)

9 Formation of Diazonium Salts and the Sandmeyer eaction ' ' Diazonium salt Diazo compound Azide S 4 / Synthetically seldom useful prim alkylamine very unstable u 2 u Substitution 2 S 4 / 2 Y Aryl amine elatively stable Diazo couplng Y Y:, 2

10 Diazotation of primary amine 2 nitrous acid (salpetersyrling) dinitrogen trioxide + 2 Ar 2 Ar Ar itrosoamine taut Ar Sec amine gives nitroso compound Ar + 2 Ar Ar itrosoamine Amines with acidic a- may give diazo compounds ' 2 C 2 2 C ' - 2 C

11 Toxicity nitroso compounds (not in McM) - Alkylation of biomolecules 2 / 3 endoplasmatic reticulum 3 C 3 C CYP450 enzyme 3 C C C 3 C 3 C sec alkylamine C 3 3 C 3 C C 3 S 2 C 3-7 alkylation of guanine in DA S-methylated cysteine in a peptide/protein

12 I C CuC ai or KI Br + / 2 or CuBr CuCl Cl 2 as leaving group Cu 2 / Cu( 3 ) 2 2 BF 4 3 P 4 F S1 like mechanism or radical mechanism u u Cu - 2 Cu 2+ Cu + Cu-salt mediated react. Sandmeyer react. (radical mech.)

13 Diazo coupling Y Phenol Aniline der (eactive u) + Electrophile Electrophilic Aromatic subst. Y Base Y Azo dyes Bayer etc Late 1800-century, ex. 3 S Metylorange 2 Pararødt Metylorange 3 S 3 S p < 3.1 p >4.4

14 Azo dyes Bayer etc Late 1800-century, ex. 3 S Metylorange Screening of dyes as antibacterials 2 Pararødt 1932: Prontocil active against Streptoccocces infection no activity on bacterial cultures 2 S : Prontocil metabilized (azoreductase) to Sulfanilamid in vivo 2 S 2 (rel. toxisk) Antibacterial sulfonamides Modern sulfa drugsr S 2 : Aryl or hetroaryl

15 eterocycles (McM chapt 24) Monocyclic or fused rings Cont. one ore more ring atom C (normally ; ; S) Aromatic, partly saturated or saturated ring(s) 5-Membered rings (eteroatom,, S) S Thiophene Pyrrole Thiophene ther examples Imidazole S Thiazole Indole 2 Adenine (purine der.) 2 =C 2 : istidine =: istamine 3 C S 2 Thiamin (Vit B1) C 3 '' = '= '''= ' = '=C 2 '''= Serotonin =Ac '= '''=C 3 Tryptophane Melatonin

16 Criteria for Aromaticity (ückel) (Monocyclic) ring Planar o of π-electrons in conjugation 4n+2 (n: 0, 1, 2,...) Cyclopentadienyl anion S S Thiophene : S, Se e - in d-orb.

17 Benzene 6 π electrons Energy Cyclobutadiene 4 π electrons Diradical Cyclopentadienyl anion 6 π electrons Thiophene 6 π electrons S All π electrons in the bonding M

18 5-membered rings - electron rich on C - reactive i E-fil. Ar subst. : S, Se e - in d-orb. + E E E E E + E E E E eact. in α-position generally preferred Selectivity not always good eact.: Pyrrole > thiophene > furan

19 6-Membered rings (eteroatom ) Pyridine ther examples Quinoline Pyrimidine Pyrazine Pyridazine are in nature 3 C Quinine 2 Cytosine Ant pheremone 2 ydralazine Antihypertensive drug

20 Pyridine as a base + pka: 5.2 sp 2 less basic than sp 3 S pka 0.4 pka 11.3 pka 7.1 ( amidine) pka 2.5

21 Electrophilic eaction on Carbon: E-phil. Ar. Subs. 6-membered rings - electron deficient on C - reactivity + E E E E + res. forms Both C and may react 3/5 pos. most reactive C Diazines less reactive Sulfonation, itration, halogenatil ot FC react.

22 ucleophilic Aromatic Substitution S Ar u u u u u S 1: Via arylic cation Benzyne S1: Involves radicals VS: Vicarious nucl. Subst. 6-membered rings - electron deficient - reactive in u-fil. Ar subst. Cl Me Me Cl Me + res. form 2 / 4 Pos. reactive; electron def. C, neg. charge partly on in intermed 3 / 5-Pos. much less reactive (benzenoid pos.)

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